Compositions and methods for treating conditions related to elevated levels of eosinophils and/or basophils

ABSTRACT

Disclosed herein are methods of treating conditions, which may be associated with elevated levels of eosinophils and/or basophils, with a therapeutically effective amount of dexpramipexole or pharmaceutical acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/904,058, filed Jan. 8, 2016, which is a U.S. national stage filingunder 35 U.S.C. § 371 of International Application No. PCT/US2014/046380filed Jul. 11, 2014, which claims priority to U.S. ProvisionalApplication No. 61/845,944 filed Jul. 12, 2013, U.S. ProvisionalApplication No. 61/859,158 filed Jul. 26, 2013, U.S. ProvisionalApplication No. 61/865,118 filed Aug. 12, 2013 and U.S. ProvisionalApplication No. 61/987,117 filed May 1, 2014. International ApplicationNo. PCT/US2014/046380 is a continuation-in-part of InternationalApplication No. PCT/US2013/054804 filed Aug. 13, 2013, which claimspriority to U.S. Provisional Application No. 61/845,944 filed Jul. 12,2013, U.S. Provisional Application No. 61/859,158 filed Jul. 26, 2013and U.S. Provisional Application No. 61/865,118 filed Aug. 12, 2013.International Application No. PCT/US2014/046380 is acontinuation-in-part of U.S. application Ser. No. 13/966,229 filed Aug.13, 2013, issued as U.S. Pat. No. 9,468,630 on Oct. 18, 2016, whichclaims priority to U.S. Provisional Application No. 61/845,944 filedJul. 12, 2013, U.S. Provisional Application No. 61/859,158 filed Jul.26, 2013, U.S. Provisional Application No. 61/865,118 filed Aug. 12,2013. Each of which are hereby incorporated by reference in theirentireties.

SUMMARY

Embodiments of the present invention relate to methods of treating acondition in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of dexpramipexole or apharmaceutically acceptable salt thereof, wherein the condition istreated. In some embodiments, the levels of eosinophils, basophils or acombination thereof in the subject is reduced following administrationto the subject of a therapeutically effective amount of dexpramipexoleor a pharmaceutically acceptable salt thereof.

Embodiments of the present invention relate to methods of treating acondition associated with granulocytes in a subject in need thereofcomprising administering to the subject a therapeutically effectiveamount of dexpramipexole (also known as(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazolediamine), or apharmaceutically acceptable salt thereof, such as,(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6-benzothiazolediaminedihydrochloride monohydrate, wherein the subject's level of granulocytesis reduced. In certain embodiments, the granulocytes are selected fromeosinophils, basophils and a combination thereof.

Some embodiments are directed to methods of treating a conditioncharacterized by elevated levels of eosinophils and/or basophils in asubject comprising administering to the subject in need thereof atherapeutically effective amount of dexpramipexole or a pharmaceuticallyacceptable salt thereof, wherein the level of eosinophils and/orbasophils are reduced. In some embodiments, the condition ischaracterized by elevated levels of eosinophils and/or basophils in theperipheral blood, tissue, or a combination thereof. In some embodiments,a condition characterized by elevated levels of eosinophils ischaracterized by levels of eosinophils above about 300 cells permicroliter in the peripheral blood. In some embodiments, a conditioncharacterized by elevated levels of basophils is characterized by levelsof basophils above about ≥100 cells per microliter in the peripheralblood.

In some embodiments, the condition is hypereosinophilic syndrome.

In some embodiments, the condition is chronic sinusitis with nasalpolyps.

In some embodiments, the condition is asthma. In some embodiments,asthma is selected from atopic asthma, allergic asthma, persistentasthma, mild asthma, moderate asthma, severe asthma and combinationsthereof.

In some embodiments, the therapeutically effective amount ofdexpramipexole or a pharmaceutically acceptable salt thereof is fromabout 50 mg to about 1,500 mg per day. In some embodiments, thetherapeutically effective amount is from about 100 mg to about 1,500 mgper day. In some embodiments, the therapeutically effective amount isfrom about 150 mg to about 1,500 mg per day. In some embodiments, thetherapeutically effective amount is from about 300 mg to about 1,500 mgper day. In some embodiments, the therapeutically effective amount isfrom about 50 mg to about 300 mg per day. In some embodiments, thetherapeutically effective amount is from about 100 mg to about 600 mgper day. In some embodiments, the therapeutically effective amount isfrom about 150 mg to about 600 mg per day. In some embodiments, thetherapeutically effective amount is from about 300 mg to about 600 mgper day.

In some embodiments, administering a therapeutically effective amountcomprises administering the daily dose as a fraction of the daily dose(as described herein) two or more times per day. In some embodiments,administering a therapeutically effective amount comprises administeringa dose equal to about half of a daily dose twice per day. In someembodiments, the dose is administered every about 12 hours. In someembodiments, administering a therapeutically effective amount comprisesadministering about 75 mg two times per day. In some embodiments,administering a therapeutically effective amount comprises administeringabout 25 mg two times per day, about 75 mg two times per day, about 150mg two times per day or about 300 mg two times per day.

Some embodiments further comprise administering to the subject atherapeutically effective amount of one or more secondary agentsselected from a corticosteroid, a non-steroidal anti-inflammatory drug(NSAID), a tyrosine kinase inhibitor, a fusion protein, a monoclonalantibody directed against one or more pro-inflammatory cytokines, achemotherapeutic agent, or a combination thereof.

Various embodiments may also comprise an induction step. In someembodiments, said induction step comprises administering to said subjecta therapeutically effective amount of a secondary agent capable ofdecreasing levels of eosinophils and/or basophils in the subject priorto administration of a therapeutically effective amount ofdexpramipexole. In some embodiments, the secondary agent isdexpramipexole. In some embodiments, the secondary agent is selectedfrom a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), atyrosine kinase inhibitor, a fusion protein, a monoclonal antibodydirected against one or more pro-inflammatory cytokines, achemotherapeutic agent, or a combination thereof. In some embodiments,said induction step comprises administering a therapeutically effectiveamount of a secondary agent for a period of about 1 day to about 6months.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 depicts the dose- and time-dependent effects of dexpramipexole oneosinophil counts from minipigs. The reduction of eosinophils wasobserved in minipigs in long-term toxicity studies (n=5-9 dosegroup/treatment interval).

FIG. 2A depicts the dose-dependent effect of dexpramipexole oneosinophil counts in the Phase 2 trial CL201 (n=22-25 per group). InFIG. 2A the time period marked “W” represents the end of the 4-weekwashout following the month 3 time point. FIG. 2B depicts thetime-dependent effect of dexpramipexole on eosinophil counts in thePhase 3 trial EMPOWER. (Mean±SEM, N=474 at baseline, N=328 at 12 monthsin dexpramipexole group, 467 and 340 in placebo group).

FIG. 3A depicts the time-dependent effects of dexpramipexole onbasophils in the Phase 3 trial. FIG. 3B depicts the effects ofdexpramipexole on neutrophils in the Phase 3 trial. (Mean±SEM, N=474 atbaseline in dexpramipexole group, 468 in placebo group).

FIG. 4A shows that dexpramipexole decreases eosinophils in a subject inthe Phase 2 study with a high baseline eosinophil count. FIG. 4B showsthat dexpramipexole decreases eosinophils in a subject in the Phase 3trial with a high baseline eosinophil count.

FIG. 5 shows the change in complete blood counts (CBC) in dexpramipexoleand placebo groups from baseline to month 6 in the Phase 3 trial.

FIG. 6 depicts the effects of dexpramipexole in an ovalabumin pulmonaryinflammation mouse model.

DETAILED DESCRIPTION

Granulocytes are white blood cells containing cytoplasmic granules andare generated from progenitor cells in the bone marrow. Upon certainchallenges, such as allergen exposure and infection, the inflammatoryresponse may include the stimulation of granulocyte production and theirrelease from the bone marrow, their entry into the bloodstream, theirmigration to target tissues, and their release, through degranulation,of cytotoxic granules. While granulocyte recruitment and activationrepresents a normal and appropriate response to an inflammatorychallenge, many pathological states are associated with granulocytes,including significantly elevated levels of granulocytes in the blood.

Various types of granulocytes have evolved to provide host defensemechanisms. These cellular types include eosinophils and basophils. Alarge number of conditions have been associated with elevated levels ofeosinophils and/or basophils, individually and in combination.

As dexpramipexole was well-tolerated in humans following exposures up to18 months, it may represent a novel therapeutic approach for thetreatment of conditions associated with elevated levels of eosinophilsand/or basophils.

Methods and pharmaceutical compositions to reduce levels of granulocytescould address significant and persistent unmet medical needs, includingin allergic and inflammatory diseases. These conditions may beassociated with elevated levels of eosinophils and/or basophils.Elevated levels of eosinophils in particular have been associated withmany human and veterinary diseases.

Inflammatory and allergic conditions associated with elevated levels ofeosinophils and/or basophils are treated primarily with corticosteroids.While often initially effective at ameliorating condition signs andsymptoms, corticosteroids exhibit significant side effect profiles,particularly during the extended periods of administration required totreat chronic inflammatory conditions. Moreover, many subjects becomerefractory to corticosteroid treatment.

In some conditions associated with elevated levels of eosinophils and/orbasophils, such as hypereosinophilic syndrome, subjects may requiretreatment with toxic chemotherapeutic or biologic agents, such ashydroxyurea and interferon α. In other conditions associated withelevated levels of eosinophils and/or basophils, such as chronicsinusitis with nasal polyps, subjects may require surgical intervention.In asthma, one of the most prevalent conditions associated with elevatedlevels of eosinophils and/or basophils, insufficient condition controlis associated with massive loss in workplace productivity and lostschool days for children.

A number of biologic therapies have been approved or remain indevelopment for various conditions associated with elevated levels ofeosinophils and/or basophils. However, these treatments generallyrequire in-clinic administration, may cause immunological reactions,including the production of neutralizing antibodies, and may causeinjection-site pain.

Accordingly, a major need exists for a small molecule agent withestablished preclinical and clinical safety experience for the treatmentof conditions associated with elevated levels of eosinophils and/orbasophils.

Dexpramipexole ((6R)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole), is a synthetic aminobenzothiazole derivative with thefollowing structure:

As used herein, dexpramipexole may be administered as a free base of apharmaceutical acceptable salt. Pharmaceutical acceptable salts include,but are not limited to, any acid addition salt, preferably apharmaceutically acceptable acid addition salt, including, but notlimited to, halogenic acid salts such as hydrobromic, hydrochloric,hydrofloric and hydroiodic acid salt; an inorganic acid salt such as,for example, nitric, perchloric, sulfuric and phosphoric acid salt; anorganic acid salt such as, for example, sulfonic acid salts(methanesulfonic, trifluoromethan sulfonic, ethanesulfonic,benzenesulfonic or p-toluenesufonic, acetic, malic, fumaric, succinic,citric, benzonic gluconic, lactic, mandelic, mucic, pamoic, pantothenic,oxalic and maleic acid salts; and an amino acid salt such as aspartic orglutamic acid salt. The acid addition salt may be a mono- or di-acidaddition salt, such as a di-hydrohalogic, di-sulfuric, di-phosphoric ordi-organic acid salt. In all cases, the acid addition salt is used as anachiral reagent which is not selected on the basis of any expected orknown preference for the interaction with or precipitation of a specificoptical isomer of the products of this disclosure.

Although any methods and materials similar or equivalent to thosedescribed herein can be used in the practice or testing of embodimentsof the present invention, the exemplary methods, devices, and materialsare now described.

In each of the embodiments described herein, the method may compriseadministering a therapeutically effective amount of dexpramipexole or apharmaceutically acceptable salt thereof. In each of the embodimentsdescribed herein, the method may consist essentially of administering atherapeutically effective amount of dexpramipexole or a pharmaceuticallyacceptable salt thereof. In each of the embodiments described herein,the method may consist of administering a therapeutically effectiveamount of dexpramipexole or a pharmaceutically acceptable salt thereof.The term “comprising” means “including, but not limited to.” The term“consisting essentially of” means the method or composition includes thesteps or components specifically recited, and may also include thosethat do not materially affect the basic and novel characteristics of thepresent invention. The term “consisting of” means the method orcomposition includes only the steps or components specifically recited.

In each of the embodiments disclosed herein, the compounds and methodsmay be utilized with or on a subject in need of such treatment, whichmay also be referred to as “in need thereof.” As used herein, the phrase“in need thereof” means that the subject has been identified as having aneed for the particular method or treatment and that the treatment hasbeen given to the subject for that particular purpose.

As used herein, the term “patient” and “subject” are interchangeable andmay be taken to mean any living organism, which may be treated withcompounds of the present invention. As such, the terms “patient” and“subject” may include, but is not limited to, any non-human mammal,primate or human. In some embodiments, the “patient” or “subject” is anadult, child, infant, or fetus. In some embodiments, the “patient” or“subject” is a human. In some embodiments, the “patient” or “subject” isa mammal, such as mice, rats, other rodents, rabbits, dogs, cats, swine,cattle, sheep, horses, primates, or humans.

As used herein, the term “eosinophil” refers to an eosinophilgranulocyte. In some embodiments, the term “eosinophil” refers to ahuman eosinophil progenitor (hEoP). In some embodiments, the term“eosinophil” refers to an eosinophil lineage-committed progenitor (EoP).In some embodiments, the term “eosinophil” refers to a human commonmyeloid progenitor (hCMP). In some embodiments, the term “eosinophil”refers to any combination of an eosinophil granulocyte, a humaneosinophil progenitor (hEoP), an eosinophil lineage-committed progenitor(EoP), and a human common myeloid progenitor (hCMP). In someembodiments, the term “eosinophil” refers to a CD34+ CD125+ progenitorcell. In some embodiments, the term “eosinophil” refers to an eosinophilresiding in the bone marrow, in the systemic circulatory system, and/orin organ tissues. In some embodiments, the organ tissue is the lung, theskin, the heart, the brain, the eye, the gastrointestinal tract, thethymus, the spleen, the ear, the nose or combinations thereof.

As used herein, the term “basophil” refers to a basophil granulocyte. Insome embodiments, the term “basophil” refers to a human basophilprogenitor. In some embodiments, the term “basophil” refers to abasophil lineage-committed progenitor. In some embodiments, the term“basophil” refers to a human common myeloid progenitor (hCMP). In someembodiments, the term “basophil” refers to any combination of anbasophil granulocyte, a human basophil progenitor, a basophillineage-committed progenitor, and a human common myeloid progenitor(hCMP). In some embodiments, the term “basophil” refers to a basophilresiding in the bone marrow, in the systemic circulatory system, and/orin organ tissues. In some embodiments, the organ tissue is the lung, theskin, the heart, the brain, the eye, the gastrointestinal tract, thethymus, the spleen, the ear, the nose or combinations thereof.

As used herein, a condition characterized by elevated levels ofeosinophils and/or basophils in a subject refers to a condition in whichthe numbers of eosinophils and/or basophils, as the case may be, areincreased or raised compared with a normal subject or are increased orraised compared to another subject with the same condition.

As used herein, the terms “adjunctive administration” and “adjunctively”may be used interchangeably, and refer to simultaneous administration ofmore than one compound in the same dosage form, simultaneousadministration in separate dosage forms, and separate administration ofmore than one compound as part of a single therapeutic regimen.

As used herein, the term “antibody” may be used to include antibody andantibody fragments such as, Fab, Fab′, F(ab′)2, scFv, dsFv, ds-scFv,dimers, minibodies, diabodies, bispecific antibody fragments, multimers,and any combination thereof, and fragments from recombinant sourcesand/or produced in transgenic animals. The antibody or fragment may befrom any species including mice, rats, rabbits, hamsters and humans.Chimeric antibody derivatives, i.e., antibody molecules that combine anon-human animal variable region and a human constant region are alsocontemplated within the scope of the invention. Chimeric antibodymolecules may include, for example, humanized antibodies which comprisethe antigen binding domain from an antibody of a mouse, rat, or otherspecies, with human constant regions. Conventional methods may be usedto make chimeric antibodies. It is expected that chimeric antibodieswould be less immunogenic in a human subject than the correspondingnon-chimeric antibody.

As used herein, the term “a no observable adverse effect level” (NOAEL)dose refers to an amount of active compound or pharmaceutical agent thatproduces no statistically, clinically or biologically significantincreases in the frequency or severity of adverse effects between anexposed population and its appropriate control; some effects may beproduced at this level, but they are not considered as adverse, or asprecursors to adverse effects. The exposed population may be a system,tissue, animal, individual or human being treated by a researcher,veterinarian, medical doctor, or other clinician.

Before the present compositions and methods are described, it is to beunderstood that this invention is not limited to the particularprocesses, compositions, or methodologies described, as these may vary.Moreover, the processes, compositions, and methodologies described inparticular embodiments are interchangeable. Therefore, for example, acomposition, dosages regimen, route of administration, and so ondescribed in a particular embodiments may be used in any of the methodsdescribed in other particular embodiments. It is also to be understoodthat the terminology used in the description is for the purpose ofdescribing the particular versions or embodiments only, and is notintended to the limit the scope of the present invention which will belimited only by the appended claims. Unless defined otherwise, alltechnical and scientific terms used herein have the same meanings ascommonly understood by one of the ordinary skill in the art. Althoughany methods similar or equivalent to those describe herein can be usedin the practice or testing of embodiments of the present invention, thepreferred methods are now described. All publications and referencesmentioned herein are incorporated by reference. Nothing herein is to beconstrued as an admission that the invention is not entitled to antedatesuch disclosure by virtue of prior invention.

It must be noted that, as used herein, and in the appended claims, thesingular forms “a”, “an” and “the” include plural reference unless thecontext clearly dictates otherwise.

As used herein, the term “about” means plus or minus 10% of thenumerical value of the number with which it is being used. Therefore,about 50% means in the range of 45%-55%.

“Optional” or “optionally” may be taken to mean that the subsequentlydescribed structure, event or circumstance may or may not occur, andthat the described includes instances where the event occurs andinstances where it does not.

“Administering” when used in conjunction with a therapeutic means toadminister a therapeutic directly or indirectly into or onto a targettissue to administer a therapeutic to a patient whereby the therapeuticpositively impacts the tissue to which it is targeted. “Administering” acomposition may be accomplished by oral administration, injection,infusion, inhalation, absorption or by any method in combination withother known techniques. “Administering” may include the act ofself-administration or administration by another person such as a healthcare provider.

The term “improves” is used to convey that the present invention changeseither the appearance, form, characteristics, structure, function and/orphysical attributes of the tissue to which it is being provided, appliedor administered. “Improves” may also refer to the overall physical stateof an individual to whom an active agent has been administered. Forexample, the overall physical state of an individual may “improve” ifone or more symptoms of the disease, condition or disorder arealleviated by administration of an active agent.

As used here, the term “therapeutic” means an agent utilized to treat,combat, ameliorate or prevent an unwanted disease, condition or disorderof a patient.

The terms “therapeutically effective amount” or “therapeutic dose” isused herein are interchangeable and may refer to the amount of an activeagent or pharmaceutical compound or composition that elicits a clinical,biological or medicinal response in a tissue, system, animal, individualor human that is being sought by a researcher, veterinarian, medicaldoctor or other clinical professional. A clinical, biological or medicalresponse may include, for example, one or more of the following: (1)preventing a disease, condition or disorder in an individual that may bepredisposed to the disease, condition or disorder but does not yetexperience or display pathology or symptoms of the disease, condition ordisorder, (2) inhibiting a disease, condition or disorder in anindividual that is experiencing or displaying the pathology or symptomsof the disease, condition or disorder or arresting further developmentof the pathology and/or symptoms of the disease, condition or disorder,and (3) ameliorating a disease, condition or disorder in an individualthat is experiencing or exhibiting the pathology or symptoms of thedisease, condition or disorder or reversing the pathology and/orsymptoms experience or exhibited by the individual.

The term “treating” may be taken to mean prophylaxis of a specificdisorder, disease or condition, alleviation of the symptoms associatedwith a specific disorder, disease or condition and/or prevention of thesymptoms associated with a specific disorder, disease or condition. Insome embodiments, the term refers to slowing the progression of thedisorder, disease or condition or alleviating the symptoms associatedwith the specific disorder, disease or condition. In some embodiments,the term refers to alleviating the symptoms associated with the specificdisorder, disease or condition. In some embodiments, the term refers toalleviating the symptoms associated with the specific disorder, diseaseor condition. In some embodiments, the term refers to restoring functionwhich was impaired or lost due to a specific disorder, disorder orcondition.

As used herein, the terms “enantiomers,” “steresiosomers,” and “opticalisomers may be used interchangeably and refer to molecules which containan asymmetric or chiral center and are mirror images of one another.Further, the terms “enantiomers,” “stereoisomers,” or “optical isomers”describe a molecule which, in a given configuration, cannot besuperimposed on its mirror images.

As used herein, the terms “optically pure” or “enantiomerically pure”may be taken to indicate that a composition contains at least 99.95% ofa single optical isomer of a compound. The term “enantiomericallyenriched” may be taken to indicate that a least 51% of a composition ina single optical isomer or enantiomer. The term “enantiomericenrichment” as used herein refer to an increase in the amount of oneenantiomer as compared to the other. A “racemic” mixture is a mixture ofabout equal amounts of (6R) and (6S) enantiomers of a chiral molecule.

Throughout this disclosure, the word “pramipexole” will refer to (6S)enantiomer of 2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazoleunless otherwise specified.

The term “pharmaceutical composition” shall mean a composition includingat least one active ingredient, whereby the composition is amenable toinvestigation for a specified, efficacious outcome in a mammal (forexample, without limitation, a human). Those of ordinary skill in theart will understand and appreciate the techniques appropriate fordetermining whether an active ingredient has a desired efficaciousoutcome based upon the needs of the artisan. A pharmaceuticalcomposition may, for example, contain dexpramipexole or apharmaceutically acceptable salt of dexpramipexole as the activeingredient. Alternatively, a pharmaceutical composition may containdexpramipexole or a pharmaceutically acceptable salt of dexpramipexoleas the active ingredient.

“Pharmaceutically acceptable salt” is meant to indicate those saltswhich are, within the scope of sound medical judgment, suitable for usein contact with the tissues of a patient without undue toxicity,irritation, allergic response and the like, and are commensurate with areasonable benefit/risk ratio. Pharmaceutically acceptable salts arewell known in the art. For example, Berge et al. (1977) J. Pharm.Sciences, Vol 6. 1-19, describes pharmaceutically acceptable salts indetail. A pharmaceutical acceptable “salt” is any acid addition salt,preferably a pharmaceutically acceptable acid addition salt, including,but not limited to, halogenic acid salts such as hydrobromic,hydrochloric, hydrofloric and hydroiodic acid salt; an inorganic acidsalt such as, for example, nitric, perchloric, sulfuric and phosphoricacid salt; an organic acid salt such as, for example, sulfonic acidsalts (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic,benzenesulfonic or p-toluenesufonic, acetic, malic, fumaric, succinic,citric, benzonic gluconic, lactic, mandelic, mucic, pamoic, pantothenic,oxalic and maleic acid salts; and an amino acid salt such as aspartic orglutamic acid salt. The acid addition salt may be a mono- or di-acidaddition salt, such as a di-hydrohalogic, di-sulfuric, di-phosphoric ordi-organic acid salt. In all cases, the acid addition salt is used as anachiral reagent which is not selected on the basis of any expected orknown preference for the interaction with or precipitation of a specificoptical isomer of the products of this disclosure.

As used herein, the term “daily dose amount” refers to the amount ofdexpramipexole per day that is administered or prescribed to a patient.This amount can be administered in multiple unit doses or in a singleunit does, in a single time during the day or at multiple times duringthe day

Embodiments of the present invention relate to methods of treating acondition in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of dexpramipexole or apharmaceutically acceptable salt thereof, wherein the condition istreated. In some embodiments, the levels of eosinophils, basophils or acombination thereof in the subject is reduced following administrationto the subject of a therapeutically effective amount of dexpramipexoleor a pharmaceutically acceptable salt thereof.

Embodiments of the present invention relate to methods of treating acondition in a subject in need thereof comprising administering to thesubject a therapeutically effective amount of dexpramipexole or apharmaceutically acceptable salt thereof, wherein the subject's level ofgranulocytes is reduced. In certain embodiments, the granulocytes areselected from eosinophils, basophils and a combination thereof.

Various embodiments described herein are directed to a method oftreating a condition characterized by normal levels of eosinophilsand/or basophils or elevated levels of eosinophils and/or basophils in asubject in need thereof comprising administering to the subject atherapeutically effective amount of dexpramipexole, or apharmaceutically acceptable salt thereof, wherein the levels ofeosinophils and/or basophils are reduced. In some embodiments, thecondition is characterized by elevated levels of eosinophils and/orbasophils. In some embodiments, the condition is characterized by normallevels of eosinophils and/or basophils in tissues including, but notlimited to lung tissue, skin tissue, bone marrow, heart tissue, braintissue, peripheral nerve tissue, vascular tissue, gastrointestinaltissue, ocular tissue, aural tissue, or nasal tissue and combinationsthereof. In yet other embodiments, the condition is characterized bynormal levels of eosinophils and/or basophils in the peripheral bloodand tissues. In some embodiments, the condition is characterized byelevated levels of eosinophils and/or basophils in tissues including,but not limited to lung tissue, skin tissue, bone marrow, heart tissue,brain tissue, peripheral nerve tissue, vascular tissue, gastrointestinaltissue, ocular tissue, aural tissue, or nasal tissue and combinationsthereof. In yet other embodiments, the condition is characterized byelevated levels of eosinophils and/or basophils in the peripheral bloodand tissues.

In some embodiments, the condition is characterized by normal levels ofeosinophils or elevated levels of eosinophils. In some embodiments, thecondition is characterized by normal levels of basophils or elevatedlevels of basophils. In some embodiments, the condition is characterizedby elevated levels of basophils with normal levels of eosinophils. Inother embodiments, the condition is characterized by elevated levels ofeosinophils with normal levels of basophils. In other embodiments, thecondition is characterized by elevated levels of basophils and elevatedlevels of eosinophils. In other embodiments, the condition ischaracterized by normal levels of basophils and normal levels ofeosinophils. In the foregoing embodiments, the normal or elevated levelsof eosinophils and/or basophils (as the case may be) may be in tissuesincluding, but not limited to lung tissue, skin tissue, bone marrow,heart tissue, brain tissue, peripheral nerve tissue, vascular tissue,gastrointestinal tissue, ocular tissue, aural tissue, or nasal tissueand combinations thereof. In the foregoing embodiments, the normal orelevated levels of eosinophils and/or basophils (as the case may be) maybe in the peripheral blood and tissues.

In some embodiments, the condition is characterized by elevated levelsof eosinophils and/or basophils in the peripheral blood, tissue, or acombination thereof. In some embodiments, the condition is characterizedby elevated levels of eosinophils and/or basophils in tissue. In someembodiments, the condition is characterized by elevated levels ofeosinophils and/or basophils in tissues including, but not limited tolung tissue, skin tissue, bone marrow, heart tissue, brain tissue,peripheral nerve tissue, vascular tissue, gastrointestinal tissue,ocular tissue, aural tissue, or nasal tissue and combinations thereof.In yet other embodiments, the condition is characterized by elevatedlevels of eosinophils and/or basophils in the peripheral blood andtissues.

In some embodiments, treating the condition results in a reduction ofthe levels of eosinophils and/or basophils. In some embodiments, thereduction of the levels of eosinophils and/or basophils is in theperipheral blood, tissue, or a combination thereof. In certainembodiments, treating the condition results in a reduction of the levelsof eosinophils and/or basophils in tissues including, but not limitedto, lung tissue, skin tissue, bone marrow, heart tissue, brain tissue,peripheral nerve tissue, vascular tissue, gastrointestinal tissue,ocular tissue, aural tissue, or nasal tissue and combinations thereof.In certain embodiments, the levels are reduced by at least 10%, at least15%, at least 20%, at least 25%, at least 30%, at least 35%, at least40%, at least 45%, at least 50%, at least 55%, at least 60%, at least65%, at least 70%, at least 75%, at least 80%, at least 85%, at least90%, at least 95%, or 100%. In certain embodiments, the levels arereduced to normal. In certain embodiments, the levels are reduced tozero within the level of detection.

In some embodiments, a subject with normal levels of eosinophils is asubject with levels of eosinophils considered to be within the normalrange or limits for the particular subject and/or condition. In someembodiments, a subject with normal levels of eosinophils ischaracterized by levels of eosinophils of less than about 300 cells permicroliter in the peripheral blood. In some embodiments, a subject withnormal levels of eosinophils is characterized by levels of eosinophilsof less than about 200 cells per microliter in the peripheral blood. Insome embodiments, a subject with normal levels of eosinophils ischaracterized by levels of eosinophils of less than about 150 cells permicroliter in the peripheral blood. In some embodiments, a subject withnormal levels of eosinophils is characterized by levels of eosinophilsof less than about 100 cells per microliter in the peripheral blood. Insome embodiments, a subject with elevated levels of eosinophils is asubject with levels of eosinophils considered to be outside of thenormal range or limit for the particular subject and/or condition. Insome embodiments, a condition characterized by elevated levels ofeosinophils is characterized by levels of eosinophils above about 300cells per microliter in the peripheral blood. In yet other embodiments acondition characterized by elevated levels of eosinophils ischaracterized by levels of eosinophils selected from above about 300cells per microliter in the peripheral blood, about 350 cells permicroliter in the peripheral blood, about 400 cells per microliter inthe peripheral blood, about 450 cells per microliter in the peripheralblood, about 500 cells per microliter in the peripheral blood, about 600cells per microliter in the peripheral blood, about 700 cells permicroliter in the peripheral blood, about 800 cells per microliter inthe peripheral blood, about 900 cells per microliter in the peripheralblood, about 1,000 cells per microliter in the peripheral blood, about1,100 cells per microliter in the peripheral blood, about 1,200 cellsper microliter in the peripheral blood, about 1,300 cells per microliterin the peripheral blood, about 1,400 cells per microliter in theperipheral blood, and about 1,500 cells per microliter in the peripheralblood. In some embodiments, the condition is hypereosinophilic syndrome,which can be characterized by levels of eosinophils above or about 1,000cells per microliter in the peripheral blood. In some embodiments, thecondition is hypereosinophilic syndrome, which can be characterized bylevels of eosinophils above or about 1,500 cells per microliter in theperipheral blood.

In some embodiments, a subject with normal levels of basophils is asubject with levels of basophils considered to be within the normalrange or limits for the particular subject and/or condition. In someembodiments, a subject with normal levels of basophils is characterizedby levels of basophils of less than about 100 cells per microliter inthe peripheral blood. In some embodiments, a subject with elevatedlevels of basophils is a subject with levels of basophils considered tobe outside of the normal range or limit for the particular subjectand/or condition. In some embodiments, a condition characterized byelevated levels of basophils is characterized by levels of basophilsselected from above about 100 cells per microliter in the peripheralblood, above about 200 cells per microliter in the peripheral blood,above about 250 cells per microliter in the peripheral blood, aboveabout 300 cells per microliter in the peripheral blood, above about 400cells per microliter in the peripheral blood, and above about 500 cellsper microliter in the peripheral blood.

In some embodiments, the condition is selected from a cardiovasculardisease, a gastrointestinal disease, a fibrotic disease, a cancer, anendocrine disease, an ear, nose, throat or eye disease, a respiratorydisease, a pulmonary disease, a skin disease, a connective tissuedisease, a renal disease, a drug-induced eosinophilia, aninfection-induced disease and a combination thereof.

In some embodiments, the condition is a cardiovascular disease. In someembodiments, the cardiovascular condition is Behçet disease, incompleteKawasaki disease (iKd), eosinophil endomyocardial disease (Loefflerendocarditis), coronary restenosis, cholesterol crystal embolism, oratherosclerosis.

In some embodiments, the condition is a gastrointestinal disease. Insome embodiments, the gastrointestinal disease is sclerosingcholangitis, irritable bowel disease, ulcerative colitis, sclerosingcholangitis, eosinophilic esophagitis, eosinophilic gastroenteritis,inflammatory bowel diseases, eosinophilic colitis, gluten sensitivity,or Cronkhite-Canada syndrome.

In some embodiments, the condition is a connective tissue disease. Insome embodiments, the connective tissue disease is systemic sclerosis,polymyositis, dermatomyositis, systemic lupus erythematosus, orrheumatoid arthritis. In some embodiments, the connective tissue diseaseis Shulman's syndrome (eosinophilic fasciitis), retroperitonealfibrosis, eosinophilia myalgia syndrome, or eosinophilic polymyositis.In some embodiments, the connective tissue disease is chronicgranulomatous disease, Wegener's vasculitis and ANCA-associatedvasculitis.

In some embodiments the condition is a cancer. In some embodiments, thecancer is angioimmunoblastic T-cell lymphoma, Sezary syndrome (cutaneousT-cell lymphoma), mantle cell lymphoma, Hodgkin lymphoma, non-Hodgkinlymphoma, adult T-cell leukemia/lymphoma, B-cell lymphoblastic leukemia,acute myeloid leukemia, acute promyelocytic leukemia, acute eosinophilicleukemia, acute basophilic leukemia, acute basophilic granulocyticleukemia, acute monocytic leukemia, acute lymphocytic leukemia, chronicmyeloid leukemia, chronic promyelocytic leukemia, chronic eosinophilicleukemia, chronic basophilic leukemia, basophilic chronic granulocyticleukemia with hyperhistaminaemia, chronic basophilic granulocyticleukemia, chronic monocytic leukemia or large cell lymphoma.

In some embodiments, the condition is eosinophilic dermatosis associatedwith a hematological malignancy such as but not limited to mantle celllymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, adult T-cellleukemia/lymphoma, B-cell lymphoblastic leukemia, acute myeloidleukemia, acute promyelocytic leukemia, acute eosinophilic leukemia,acute basophilic leukemia, acute basophilic granulocytic leukemia, acutemonocytic leukemia, acute lymphocytic leukemia, chronic myeloidleukemia, chronic promyelocytic leukemia, chronic eosinophilic leukemia,chronic basophilic leukemia, basophilic chronic granulocytic leukemiawith hyperhistaminaemia, chronic basophilic granulocytic leukemia,chronic monocytic leukemia, large cell lymphoma, myelofibrosis orchronic lymphocytic leukemia.

In some embodiments, the condition is a myeloproliferative disease. Insome embodiments, the myeloproliferative disease is aggressive systemicmastocytosis, hypereosinophilic syndrome, eosinophilic granuloma(histiocytosis X), myelofibrosis, essential thrombocythemia orpolycythemia vera.

In some embodiments, the condition is an endocrine disease. In someembodiments, the endocrine disease is eosinophilic prostatitis, Ridel'sfibrous thyroiditis, or Hashimoto's thyroiditis.

In some embodiments, the condition is an ear, nose, throat or eyedisease. In some embodiments, the ear, nose, throat or eye disease isnon-allergic rhinitis, chronic sinusitis with nasal polyposis or polyps,nasal polyposis, hyper-IgE syndrome, eosinophilic otitis media, vernalkeratoconjunctivitis, herpes stromal keratitis, Graves' ophthalmology,orbital pseudotumor, Kimura's disease, tonsillitis or cervical adenitis.

In some embodiments, the condition is a respiratory disease. In someembodiments, the respiratory disease is seasonal allergy, cypressallergy, or eosinophilic angiocentric fibrosis. In some embodiments, therespiratory disease is Churg-Strauss syndrome In some embodiments, therespiratory disease is asthma. In some embodiments, the respiratorydisease is eosinophilic asthma. In some embodiments, asthma is selectedfrom atopic asthma, allergic asthma, persistent asthma, mild asthma,moderate asthma, severe asthma, alternia-enhanced asthma andcombinations thereof. In some embodiments, the respiratory disease ischronic obstructive pulmonary disease. In some embodiments, the chronicobstructive pulmonary disease is emphysema or chronic bronchitis. Insome embodiments, the respiratory disease is acute bronchitis,eosinophilic bronchitis or bronchiectasis. In some embodiments, therespiratory disease is interstitial lung disease, sarcoidosis,idiopathic pulmonary fibrosis, Hamman-Rich syndrome, or antisynthetasesyndrome. In some embodiments, the respiratory disease is pleuraleosinophilia, bronchopulmonary aspergillosis, non-allergic rhinitis witheosinophilia syndrome, chronic eosinophilic pneumonia.

In some embodiments, the condition is a skin disease. In someembodiments, the skin disease is atopic dermatitis, chronic idiopathicurticaria, Wells' syndrome (eosinophilic cellulitis), eosinophilicpustular folliculitis, Henoch-Schönlein purpura (anaphylactoid purpura),epitheloid hemangioma, bullous pemphigoid, angiolymphoid hyperplasiawith eosinophilia, eosinophilic panniculitis, angioedema witheosinophilia, Gleich's syndrome, or Omenn syndrome.

In some embodiments the condition is a urogenital disease. In someembodiments, the urogenital disease is eosinophiluria, eosinophilicprostatitis or nephrogenic systemic fibrosis.

In some embodiments, the condition is Langerhans cell histocystosis,Erdheim-Chester disease, periodontal disease, eosinophil endomyocardialdisease (Loeffler endocarditis) or a drug-induced eosinophilia.

In some embodiments, the condition is drug-induced eosinophilia. In someembodiments, the drug-induced eosinophilia is drug rash witheosinophilia and systemic symptoms (DRESS), eosinophilic probioticreaction, eosinophilia-myalgia syndrome, minocycline-inducedeosinophilic pneumonia, or telaprevir-based triple therapy for chronichepatitis associated hypereosinophilia. In some embodiments, thecondition is DRESS resulting from the use of ipilimumab, orgranulomatous inflammation of the central nervous system resulting fromthe use of ipilimumab. In some embodiments, the condition is DRESSresulting from the use of atorvastatin, ceftazidime, carbamazepine,telaprevir, or allopurinol.

In some embodiments, the condition is an infection-induced disease. Insome embodiments, the condition is a tropical infection-induced disease.In some embodiments, the infection-induced disease is onchocerciasis(river blindness), eosinophilic meningitis, tropical sprue,paracoccidioidomycosis, cerebellar malaria or cerebral malaria.

In some embodiments, the condition is selected from eosinophilendomyocardial disease (Loeffler endocarditis), coronary restenosis,cholesterol crystal embolism, atherosclerosis, sclerosing cholangitis,irritable bowel disease, ulcerative colitis, eosinophilic colitis,gluten sensitivity, Cronkhite-Canada syndrome, Shulman's syndrome(eosinophilic faciitis), retroperitoneal fibrosis, nephrogenic systemicfibrosis, eosinophilic angiocentric fibrosis, angioimmunoblastic T-celllymphoma, Sezary syndrome (cutaneous T-cell lymphoma), eosinophilicdermatosis associated with a hematological malignancy, myelodysplasticsyndrome, eosinophiluria, pleural eosinophilia, eosinophilicpanniculitis, angioedema with eosinophilia, Kimura's disease,bronchopulmonary aspergillosis, eosinophilic prostatitis, Ridel'sfibrous thyroiditis, Hashimoto's thyroiditis, chronic sinusitis withnasal polyposis or polyps, eosinophilic otitis media, vernalkeratoconjunctivitis, orbital pseudotumor, seasonal allergies, a cypressallergy, alternaria-enhanced asthma, atopic dermatitis, chronicidiopathic urticaria, Wells' syndrome (eosinophilic cellulitis),eosinophilic pustular folliculitis, Henoch-Schönlein purpura(anaphylactoid purpura), epitheloid hemangioma, bullous pemphigoig,angiolymphoid hyperplasia with eosinophilia, reno disease, Langerhanscell histocystosis, Erdheim-Chester disease, periodontal disease, drugrash with eosinophilia and systemic symptoms (DRESS), eosinophilicprobiotic reaction, eosinophilia-myalgia syndrome, minocycline-inducedeosinophilic pneumonia, telaprevir-based triple therapy for chronichepatitis associated hypereosinophilia, DRESS resulting from the use ofipilimumab, granulomatous inflammation of the central nervous systemresulting from the use of ipilimumab, DRESS resulting from the use ofatorvastatin, ceftazidime, carbamazepine, telaprevir, or allopurinol,onchocerciasis (river blindness), eosinophilic meningitis, tropicalsprue, paracoccidioidomycosis, malaria, cerebral malaria, cerebellarmalaria, incomplete Kawasaki disease (iKd), Behçet disease, tonsolitisand cervical adenitis, Graves' ophthalmology, Churg-Strauss syndrome,nasal polyposis, eosinophilic esophagitis, hypereosinophilic syndrome,chronic granulomatous disease, Wegener's vasculitis and ANCA-associatedvasculitis, asthma, allergic rhinitis, non-allergic rhinitis,non-allergic rhinitis with eosinophilia syndrome, eosinophilic granuloma(histiocytosis X), eosinophilic polymyositis, chronic eosinophilicpneumonia, eosinophilic gastroenteritis, aggressive systemicmastocytosis, Gleich's syndrome, eosinophilia myalgia syndrome, Omennsyndrome, hyper-IgE syndrome, eosinophilic leukemia, inflammatory boweldiseases, herpes stromal keratitis, and any combination thereof.

In some embodiments, the condition is selected from eosinophilendomyocardial disease (Loeffler endocarditis), cholesterol crystalembolism, sclerosing cholangitis, irritable bowel disease, ulcerativecolitis, eosinophilic colitis, gluten sensitivity, Cronkhite-Canadasyndrome, Shulman's syndrome (eosinophilic faciitis), retroperitonealfibrosis, nephrogenic systemic fibrosis, eosinophilic angiocentricfibrosis, angioimmunoblastic T-cell lymphoma, Sezary syndrome (cutaneousT-cell lymphoma), eosinophilic dermatosis associated with ahematological malignancy, myelodysplastic syndrome, eosinophiluria,pleural eosinophilia, eosinophilic panniculitis, angioedema witheosinophilia, Kimura's disease, bronchopulmonary aspergillosis,eosinophilic prostatitis, Ridel's fibrous thyroiditis, Hashimoto'sthyroiditis, chronic sinusitis with nasal polyposis or polyps,eosinophilic otitis media, vernal keratoconjunctivitis, orbitalpseudotumor, seasonal allergies, a cypress allergy, alternaria-enhancedasthma, atopic dermatitis, chronic idiopathic urticaria, Wells' syndrome(eosinophilic cellulitis), eosinophilic pustular folliculitis,Henoch-Schönlein purpura (anaphylactoid purpura), epitheloid hemangioma,bullous pemphigoig, angiolymphoid hyperplasia with eosinophilia, renodisease, Langerhans cell histocystosis, Erdheim-Chester disease,periodontal disease, drug rash with eosinophilia and systemic symptoms(DRESS), eosinophilic probiotic reaction, eosinophilia-myalgia syndrome,minocycline-induced eosinophilic pneumonia, telaprevir-based tripletherapy for chronic hepatitis associated hypereosinophilia, DRESSresulting from the use of ipilimumab, granulomatous inflammation of thecentral nervous system resulting from the use of ipilimumab, DRESSresulting from the use of atorvastatin, ceftazidime, carbamazepine,telaprevir, or allopurinol, onchocerciasis (river blindness),eosinophilic meningitis, tropical sprue, paracoccidioidomycosis,malaria, cerebral malaria, cerebellar malaria, incomplete Kawasakidisease (iKd), Behçet disease, tonsolitis and cervical adenitis, Graves'ophthalmology, Churg-Strauss syndrome, nasal polyposis, eosinophilicesophagitis, hypereosinophilic syndrome, chronic granulomatous disease,Wegener's vasculitis and ANCA-associated vasculitis, asthma, allergicrhinitis, non-allergic rhinitis, non-allergic rhinitis with eosinophiliasyndrome, eosinophilic granuloma (histiocytosis X), eosinophilicpolymyositis, chronic eosinophilic pneumonia, eosinophilicgastroenteritis, aggressive systemic mastocytosis, Gleich's syndrome,eosinophilia myalgia syndrome, Omenn syndrome, hyper-IgE syndrome,eosinophilic leukemia, inflammatory bowel diseases, herpes stromalkeratitis, and any combination thereof.

In some embodiments, the condition is characterized by eosinophils orelevated eosinophil levels. In some embodiments, the condition isselected from the group consisting of incomplete Kawasaki disease (iKd),Behçet disease, tonsolitis and cervical adenitis, Graves' ophthalmology,Churg-Strauss syndrome, nasal polyposis, atopic dermatitis, eosinophilicesophagitis, hypereosinophilic syndrome, asthma, allergic rhinitis,non-allergic rhinitis with eosinophilia syndrome, eosinophilic granuloma(histiocytosis X), eosinophilic polymyositis, chronic eosinophilicpneumonia, eosinophilic gastroenteritis, aggressive systemicmastocytosis, Gleich's syndrome, eosinophilia myalgia syndrome, Omennsyndrome, hyper-IgE syndrome, eosinophilic leukemia, and inflammatorybowel diseases.

In some embodiments, the condition is characterized by basophils orelevated basophil levels. In some embodiments, the condition is herpesstromal keratitis.

In some embodiments, the condition is aggressive systemic mastocytosis.

In some embodiments, the condition is angioimmunoblastic T-celllymphoma, Sezary syndrome (cutaneous T-cell lymphoma), mantle celllymphoma, Hodgkin lymphoma, non-Hodgkin lymphoma, adult T-cellleukemia/lymphoma, B-cell lymphoblastic leukemia, acute myeloidleukemia, acute promyelocytic leukemia, acute eosinophilic leukemia,acute basophilic leukemia, acute basophilic granulocytic leukemia, acutemonocytic leukemia, acute lymphocytic leukemia, chronic myeloidleukemia, chronic promyelocytic leukemia, chronic eosinophilic leukemia,chronic basophilic leukemia, basophilic chronic granulocytic leukemiawith hyperhistaminaemia, chronic basophilic granulocytic leukemia,chronic monocytic leukemia, large cell lymphoma, myelofibrosis orpolycythemia vera.

In some embodiments, the eosinophilic dermatosis associated with ahematological malignancy is associated with mantle cell lymphoma,Hodgkin lymphoma, non-Hodgkin lymphoma, adult T-cell leukemia/lymphoma,B-cell lymphoblastic leukemia, acute myeloid leukemia, acutepromyelocytic leukemia, acute eosinophilic leukemia, acute basophilicleukemia, acute basophilic granulocytic leukemia, acute monocyticleukemia, acute lymphocytic leukemia, chronic myeloid leukemia, chronicpromyelocytic leukemia, chronic eosinophilic leukemia, chronicbasophilic leukemia, basophilic chronic granulocytic leukemia withhyperhistaminaemia, chronic basophilic granulocytic leukemia, chronicmonocytic leukemia, large cell lymphoma, myelofibrosis, chroniclymphocytic leukemia or a combination thereof.

In some embodiments, the condition is hypereosinophilic syndrome.

In some embodiments, the condition is chronic sinusitis with nasalpolyps.

In some embodiments, the condition is asthma. In some embodiments, thecondition is eosinophilic asthma. In some embodiments, asthma isselected from atopic asthma, allergic asthma, persistent asthma, mildasthma, moderate asthma, severe asthma and any combination thereof.

In some embodiments, the condition is a secondary response to aninfection-induced disease. In some embodiments, the condition is asecondary response to a tropical infection-induced disease. In someembodiments, the infection-induced disease is onchocerciasis (riverblindness), eosinophilic meningitis, tropical sprue,paracoccidioidomycosis, malaria, cerebellar malaria or cerebral malaria.

In another embodiment, the condition may include systemic inflammation.Systemic inflammation is not confined to a particular tissue, mayoverwhelm the body, and may involve the endothelium and other organsystems. When it is due to infection, the term sepsis may be applied,with the terms bacteremia being applied specifically as provokingbacterial sepsis and viremia specifically as provoking viral sepsis.Vasodilation and organ dysfunction are serious problems associated withsepsis that may lead to septic shock and death.

In another embodiment, the condition may be arthritis. Arthritisincludes a group of conditions involving damage to the joints of thebody often involving the inflammation of the synovium including, withoutlimitation, osteoarthritis, rheumatoid arthritis, juvenile idiopathicarthritis, spondyloarthropathies such as ankylosing spondylitis,reactive arthritis (Reiter's syndrome), psoriatic arthritis,enteropathic arthritis associated with inflammatory bowel disease,Whipple disease and Behçet disease, septic arthritis, gout (also knownas gouty arthritis, crystal synovitis, metabolic arthritis), pseudogout(calcium pyrophosphate deposition disease), and Still's disease.Arthritis can affect a single joint (monoarthritis), two to four joints(oligoarthritis) or five or more joints (polyarthritis) and can beeither an auto-immune disease or a non-autoimmune disease.

In some embodiments, the condition, disease or disorder is not aneurodegenerative disease. In some embodiments, the condition is notParkinson's disease, Alzheimer's disease or amyotrophic lateralsclerosis.

In some embodiments, the condition is a veterinary disease. In someembodiments, a veterinary disease is a disease that occurs in non-humananimals.

In some embodiments, the veterinary disease is a skin disease. In someembodiments, the skin disease is eosinophilic dermatosis, eosinophilicgranuloma complex, or mosquito bite hypersensitivity. In someembodiments, subtypes of eosinophilic granuloma complex include but arenot limited to eosinophilic plaque, eosinophilic granuloma, andeosinophilic ulcers. In some embodiments, the eosinophilic granulomacomplex is equine eosinophilic granuloma in horses or feline miliarydermatitis in cats. In some embodiments, the skin disease is felineherpesvirus dermatitis and stomatosis, canine facial eosinophilicfolliculitis and furunculosis, canine atopic dermatitis, canineeosinophilic dermatitis with edema (Wells' syndrome), or canine allergicdermatitis.

In some embodiments, the veterinary disease is a gastrointestinaldisease. In some embodiments, the gastrointestinal disease iseosinophilic gastroenteritis, feline intestinal eosinophilic sclerosingfibroplasia, or masticatory muscle myositis.

In some embodiments, the veterinary disease is a respiratory disease. Insome embodiments, the respiratory disease is feline bronchial asthma,eosinophilic bronchopneumopathy, or nasal mycotic granuloma.

In some embodiments, the veterinary disease is a systemic disease. Insome embodiments, the systemic disease is multisystemic eosinophilicepitheliotrophic disease (MEED), eosinophilic leukemia, eosinophilicmyositis, equine nodular disease, or eosinophilic keratitis.

Various embodiments are directed to a method of treating a conditioncharacterized by pathogenic basophils, eosinophils and/or neutrophils ina patient comprising administering to the patient a therapeuticallyeffective amount of(6R)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, or apharmaceutically acceptable salt thereof. In some embodiments, thecondition is characterized by increased levels of basophils, eosinophilsand/or neutrophils.

Various embodiments are directed to a method of treating a conditioncharacterized by pathogenic basophils, eosinophils or neutrophils in apatient comprising administering to the patient a pharmaceuticalcomposition comprising a therapeutically effective amount of(6R)-2-amino-4,5,6,7-tetrahydro-6-(propylamino)benzothiazole, or apharmaceutically acceptable salt thereof. In some embodiments, thecondition is characterized by increased levels of basophils, eosinophilsand/or neutrophils.

In some embodiments, the condition is an allergic condition. In stillother embodiments, the condition is an inflammatory condition. In someembodiments, the condition is selected from the group consisting ofIncomplete Kawasaki disease (iKd), Behçet Disease, tonsolitis andcervical adenitis, Graves' ophthalmology, chronic eosinophilicpneumonia, eosinophilic gastroenteritis, aggressive systemicmastocytosis, Gleich's syndrome, eosinophilia myalgia syndrome, Omennsyndrome, hyper-IgE syndrome, Churg Strauss syndrome, nasal polyposis,atopic dermatitis, eosinophilic esophagitis, hypereosinophilic syndrome,allergic rhinitis, non-allergic rhinitis with eosinophilia syndrome,eosinophilic granuloma (histiocytosis X), eosinophilic polymyositis,allergy, drug induced injuries, cutaneous reactions and disordersincluding bullous pemphigoid, chronic granulomatous disease,vasculitides including Wegener's and ANCA-associated vasculitis,intracerebral hemorrhage, spinal cord injury, traumatic brain injury,multiple sclerosis and other neuroinflammatory diseases, neuromyelitisoptica, herpes stromal keratitis, immune-mediated neurologic disorders,microglia-derived inflammation, inflammatory bowel disease, respiratorydisorders including asthma and COPD, autoimmune disorders includinginsulin dependent diabetes mellitus, systemic lupus erythematosus andrheumatoid arthritis, non-insulin dependent diabetes, dermatitisherpetiformis, parasitic infections, malaria-induced cerebellar damage,Hodgkin's lymphoma, Non-Hodgkin lymphoma, systemic autoimmune diseases,cholesterol embolism, coccidioidomycosis, ovarian cancer, andneurodegenerative disease. In some embodiments, the condition isselected from the group consisting of Incomplete Kawasaki disease (iKd),Behçet Disease, tonsolitis and cervical adenitis, Graves' ophthalmology,chronic eosinophilic pneumonia, eosinophilic gastroenteritis, aggressivesystemic mastocytosis, Gleich's syndrome, eosinophilia myalgia syndrome,Omenn syndrome, hyper-IgE syndrome, Churg Strauss syndrome, nasalpolyposis, eosinophilic esophagitis, hypereosinophilic syndrome,allergic rhinitis, non-allergic rhinitis with eosinophilia syndrome,eosinophilic granuloma (histiocytosis X), eosinophilic polymyositis,allergy, drug induced injuries, cutaneous reactions and disordersincluding bullous pemphigoid, chronic granulomatous disease,vasculitides including Wegener's and ANCA-associated vasculitis, spinalcord injury, multiple sclerosis and other neuroinflammatory diseases,neuromyelitis optica, herpes stromal keratitis, immune-mediatedneurologic disorders, microglia-derived inflammation, inflammatory boweldisease, respiratory disorders including asthma and COPD, autoimmunedisorders including insulin dependent diabetes mellitus, systemic lupuserythematosus and rheumatoid arthritis, dermatitis herpetiformis,parasitic infections, malaria-induced cerebellar damage, Hodgkin'slymphoma, Non-Hodgkin lymphoma, systemic autoimmune diseases,cholesterol embolism, coccidioidomycosis, and ovarian cancer.

In some embodiments, the condition is characterized by pathogeniceosinophils or elevated eosinophil levels. In some embodiments, thecondition is selected from the group consisting of incomplete Kawasakidisease (iKd), Behçet Disease, tonsolitis and cervical adenitis, Graves'ophthalmology, Churg Strauss, nasal polyposis, atopic dermatitis,eosinophilic esophagitis, hypereosinophilic syndrome, asthma, allergicrhinitis, non-allergic rhinitis with eosinophilia syndrome, eosinophilicgranuloma (histiocytosis X), eosinophilic polymyositis, chroniceosinophilic pneumonia, eosinophilic gastroenteritis, aggressivesystemic mastocytosis, Gleich's syndrome, eosinophilia myalgia syndrome,Omenn syndrome, hyper-IgE syndrome, as eosinophilic leukemia, andinflammatory bowel diseases.

In some embodiments, the condition is characterized by pathogenicbasophils or elevated basophil levels. In some embodiments, thecondition is selected from the group consisting of allergy, and herpesstromal keratitis.

In some embodiments, the condition is characterized by pathogenicneutrophils or elevated neutrophil levels. In some embodiments, thecondition is selected from the group consisting of drug inducedinjuries, cutaneous reactions and disorders including bullouspemphigoid, chronic granulomatous disease, vasculitides includingWegener's and ANCA-associated vasculitis, intracerebral hemorrhage,spinal cord injury, traumatic brain injury, multiple sclerosis,neuromyelitis optica, immune-mediated neurologic disorders, inflammatorybowel disease, respiratory disorders including asthma and COPD,autoimmune disorders including IDDM and SLE and rheumatoid arthritis,non-insulin dependent diabetes, herpes stromal keratitis andneurodegenerative diseases. In some embodiments, the condition isselected from the group consisting of drug induced injuries, cutaneousreactions and disorders including bullous pemphigoid, chronicgranulomatous disease, vasculitides including Wegener's andANCA-associated vasculitis, spinal cord injury, multiple sclerosis,neuromyelitis optica, immune-mediated neurologic disorders, inflammatorybowel disease, respiratory disorders including asthma and COPD,autoimmune disorders including IDDM and SLE and rheumatoid arthritis andherpes stromal keratitis.

In some embodiments, the condition is not a neurodegenerative disease.In some embodiments, the condition is not Parkinson's disease,Alzheimer's disease or amyotrophic lateral sclerosis.

In some embodiments, administering a therapeutically effective amount ofdexpramipexole or a pharmaceutically acceptable salt thereof may includeadministering daily doses of about 0.1 mg or more, about 1 mg or more,about 10 mg or more, about 50 mg or more, about 75 mg or more, about 100mg or more, about 125 mg or more, about 150 mg or more, about 175 mg ormore, about 200 mg or more, about 225 mg or more, about 250 mg or more,about 275 mg or more, about 300 mg or more, about 400 mg or more, about450 mg or more, about 500 mg or more, about 600 mg or more, about 700 mgor more, about 800 mg or more or about 1,000 mg or more, about 1,200 mgor more or about 1,500 mg or more.

In some embodiments, the therapeutically effective amount ofdexpramipexole or a pharmaceutically acceptable salt thereof is fromabout 50 mg to about 1,500 mg per day. In some embodiments, thetherapeutically effective amount is from about 100 mg to about 1,500 mgper day. In some embodiments, the therapeutically effective amount isfrom about 150 mg to about 1,500 mg per day. In some embodiments, thetherapeutically effective amount is from about 300 mg to about 1,500 mgper day. In some embodiments, the therapeutically effective amount isfrom about 50 mg to about 300 mg per day. In some embodiments, thetherapeutically effective amount is from about 150 mg to about 300 mgper day.

In some embodiments, administering a therapeutically effective amountcomprises administering the daily dose as a fraction of the daily dose(as described herein) two or more times per day. In some embodiments,administering a therapeutically effective amount comprises administeringa dose equal to about half of a daily dose twice per day. In someembodiments, the dose is administered every about 12 hours. In someembodiments, administering a therapeutically effective amount comprisesadministering about 75 mg two times per day. In some embodiments,administering a therapeutically effective amount comprises administeringabout 25 mg two times per day, about 75 mg two times per day, about 150mg two times per day, or about 300 mg two times per day.

In some embodiments, administering a therapeutically effective amountcomprises administering a single unit dose of dexpramipexole of about0.1 mg or more, about 1 mg or more, about 10 mg or more, about 25 mg ormore, about 50 mg or more, about 75 mg or more, about 100 mg or more,about 125 mg or more, about 150 mg or more, about 175 mg or more, about200 mg or more, about 225 mg or more, about 250 mg or more, about 275 mgor more, about 300 mg or more, about 400 mg or more, about 450 mg ormore, about 500 mg or more, about 600 mg or more, about 700 mg or more,about 800 mg or more, about 1,000 mg or more, about 3,000 mg or more, orabout 5,000 mg or more. In some embodiments, the single unit dosecomprises from about 600 mg to about 900 mg of dexpramipexole.

In some embodiments, administering a therapeutically effective amountcomprises administering a single unit dose amount of dexpramipexole or apharmaceutically acceptable salt thereof from about 25 mg to about 5,000mg, from about 50 mg to about 5,000 mg, from about 100 mg to about 5,000mg, from about 150 mg to about 5,000 mg, from about 200 mg to about5,000 mg, from about 250 mg to about 5,000 mg, from about 300 mg toabout 5,000 mg, from about 400 mg to about 5,000 mg, from 450 mg toabout 5,000 mg, from about 100 mg to about 3,000 mg, from about 150 mgto about 3,000 mg, from about 200 mg to about 3,000 mg, from about 250mg to about 3,000 mg, from about 300 mg to about 3,000 mg, from about400 mg to about 3,000 mg, from 450 mg to about 3,000 mg, from about 100mg to about 1,000 mg, from about 150 mg to about 1,000 mg, from about200 mg to about 1,000 mg, from about 250 mg to about 1,000 mg, fromabout 300 mg to about 1,000 mg, from about 400 mg to about 1,000 mg,from 450 mg to about 1,000 mg, from about 500 mg to about 1000 mg, fromabout 600 mg to about 1,000 mg. In some embodiments, the single unitdose amount may be 10 mg/day to 1,500 mg/day, more preferably 100 mg/dayto 600 mg/day. In some embodiments, the single unit dose amount ofdexpramipexole or a pharmaceutically acceptable salt thereof is fromabout 600 mg to about 900 mg. In some embodiments, the single unit doseamount of dexpramipexole or a pharmaceutically acceptable salt thereofis from about 300 mg to about 1,500 mg. In some embodiments, such singleunit doses may be administered once per day or multiple times per day,such as twice per day or three times per day.

In another embodiment, administering a therapeutically effective amountcomprises administering a single unit dose comprising at least about 50mg of dexpramipexole or a pharmaceutically acceptable salt thereof andno more than about 1.5 mg of (S)-pramipexole. In another aspect, thepresent invention provides a single unit dose comprising at least about75 mg of dexpramipexole or a pharmaceutically acceptable salt thereofand no more than about 1.5 mg of (S)-pramipexole, or at least about 100mg of dexpramipexole or a pharmaceutically acceptable salt thereof andno more than about 1.5 mg of (S)-pramipexole. In some embodiments, thesingle unit dose comprises no more than 1.0 mg, no more than 0.333 mg nomore than 0.3 mg no more than 0.2 mg, no more than 0.125 mg of(S)-pramipexole.

In some embodiments, the single unit dose further comprises apharmaceutically acceptable carrier. In some embodiments, such singleunit doses may be administered once per day or multiple times per day,such as twice per day or three times per day.

One of ordinary skill in the art will understand and appreciate thedosages and timing of the dosages to be administered to a subject inneed thereof. The doses and duration of treatment may vary, and may bebased on assessment by one of ordinary skill in the art based onmonitoring and measuring improvements in neuronal and non-neuronaltissues. This assessment may be made based on outward physical signs ofimprovement, such as increased muscle control, or on internalphysiological signs or markers. The doses may also depend on thecondition or disease being treated, the degree of the condition ordisease being treated and further on the age, weight, body mass indexand body surface area of the subject.

In some embodiments, therapeutically effective amounts, daily doses, orsingle unit doses of dexpramipexole may be administered once per day ormultiple times per day, such as 1 to 5 doses, twice per day or threetimes per day.

Embodiments are also directed to a dosage regimen for administeringdexpramipexole or a pharmaceutically acceptable salt thereof to treatthe conditions disclosed herein. For example, in some embodiments, themethods described herein may comprise a dosage regimen that may includea plurality of daily doses having an equal amount of dexpramipexole or apharmaceutically acceptable salt thereof as the initial dose in one ormore unit doses. In other embodiments, the dosage regimen may include aninitial dose of dexpramipexole or a pharmaceutically acceptable saltthereof in one or more unit doses, then a plurality of daily doseshaving a lower amount of dexpramipexole or a pharmaceutically acceptablesalt thereof as the initial dose in one or more unit doses. The dosageregimen may administer an initial dose followed by one or moremaintenance doses. The plurality of doses following the administering ofan initial dose may be maintenance doses.

Such embodiments are not limited by the amount of the initial dose anddaily doses. For example, in particular embodiments, the initial doseand each of the plurality of daily doses may be from about 0.1 mg ormore, about 1 mg or more, about 10 mg or more, about 50 mg or more,about 75 mg or more, about 100 mg or more, about 125 mg or more, about150 mg or more, about 175 mg or more, about 200 mg or more, about 225 mgor more, about 250 mg or more, about 275 mg or more, about 300 mg ormore, about 400 mg or more, about 450 mg or more, about 500 mg or more,about 600 mg or more, about 700 mg or more, about 800 mg or more, about1,000 mg or more, 1,200 mg or more, or about 1,500 mg or more ofdexpramipexole. In some embodiments, the one or more unit doses of thedosage regimen may be 1 to 5 unit doses, and in such embodiments, eachof the one or more unit doses may be substantially equal.

In some embodiments, two unit doses of about 75 mg are administereddaily, wherein each unit dose may be substantially equal. In someembodiments, three unit doses of about 75 mg are administered daily,wherein each unit dose may be substantially equal.

In other embodiments, the maintenance therapy dosing may includeadministering less than the initial daily dose, such as less than about50 mg, less than about 75 mg, less than about 150 mg, less than about300 mg, or less than 600 mg of dexpramipexole per day. Following theinitial dosing regimen, the subject may be administered a maintenancedosing regimen of, for example, about 0.1 mg or more, about 1 mg ormore, about 10 mg or more, about 50 mg or more, about 75 mg or more,about 100 mg or more, about 125 mg or more, about 150 mg or more, about175 mg or more, about 200 mg or more, about 225 mg or more, about 250 mgor more, about 275 mg or more, about 300 mg or more, about 400 mg ormore, about 450 mg or more, about 500 mg or more, about 600 mg or more,about 700 mg or more, about 800 mg or more, or about 1,000 mg or more,about 1,200 mg or more, or about 1,500 mg or more of dexpramipexole fora period of time such as, for example, at least 12 weeks or more or atleast 6 months or 1, 2, 3, 5 or 10 years or more.

In further embodiments, the method may include an initial dosing regimenand a maintenance dosing regimen. In certain embodiments, the initialdosing regimen may include administering a higher dose of dexpramipexoleor a pharmaceutically acceptable salt thereof than the maintenancedosing regimen as either a single administration or by administering anincreased dosage for a limited period of time prior to beginning amaintenance dosing regimen of dexpramipexole or a pharmaceuticallyacceptable salt thereof. In some embodiments, subjects undergoing amaintenance regimen may be administered one or more higher-dosagetreatments at one or more times during the maintenance dosage regimen.

In certain embodiments, the initial dosing regimen and the maintenancedosing regimen may be about 50 mg to about 1500 mg or more ofdexpramipexole, about 150 mg to about 300 mg or more of dexpramipexole,about 300 mg to about 500 mg or more of dexpramipexole per day, or fromabout 300 mg to about 600 mg or more of dexpramipexole per day.

In some embodiments, the initial dosing regimen and the maintenancedosing regimen may include administering dexpramipexole or apharmaceutically acceptable salt thereof once per day, multiple timesper day, such as twice per day or three times per day. In suchembodiments, the dosage regimen may continue administering an initialdose for 1, 2, 3, 4, 5, 6 or 7 days, up to 4 weeks, up to 8 weeks or upto 12 weeks. In some embodiments, the dosage regimen for administeringan initial dose and/or a maintenance dose may continue for an extendedperiod of time. Various embodiments are directed to a dosing regimen fordexpramipexole or a pharmaceutically acceptable salt thereof in whichmaintenance doses are maintained for an extended period of time withouttitration or otherwise changing the dosing regimen. In such embodiments,the extended period of time may be about 12 weeks or longer, about 6months or longer, about 1 year or longer, 2, 3, 4, 5, or 10 years orlonger, and in certain embodiments, an indefinite period of time.

Each of the dosage regimens for dexpramipexole described herein may beused in any of the methods, and the dosing regimen may be carried outusing any of the compositions described herein.

In some embodiments, treatment with a therapeutically effective amountof dexpramipexole is without the adverse side effects associated withdopamine agonism.

Some embodiments further comprise administering to the subject atherapeutically effective amount of one or more secondary agents. Insome embodiments, the therapeutically effective amount of dexpramipexoleor salt thereof and the therapeutically effective amount of the one ormore secondary agents may be administered individually or combined intoa single dosage composition. In some embodiments, the therapeuticallyeffective amount of dexpramipexole or salt thereof and thetherapeutically effective amount of the one or more secondary agents areadministered simultaneously or sequentially.

In some embodiments, the one or more secondary agent is any drug thatinduces anti-inflammatory effects or is capable of decreasing levels ofeosinophils and/or basophils in the subject. In some embodiments, thesecondary agent is an antibody. In some embodiments, the secondary agentis not dexpramipexole. In some embodiments, the secondary agent isselected from a corticosteroid, a non-steroidal anti-inflammatory drug(NSAID), a tyrosine kinase inhibitor, a fusion protein, a monoclonalantibody directed against one or more pro-inflammatory cytokines, achemotherapeutic agent and a combination thereof. In some embodiments,the secondary agent may be a glucocorticoid, a corticosteroid, anon-steroidal anti-inflammatory drug (NSAID), a phenolic antioxidant, ananti-proliferative drug, a tyrosine kinase inhibitor, an anti IL-5 or anIL5 receptor monoclonal antibody, an anti IL-13 or an anti IL-13receptor monoclonal antibody, an IL-4 or an IL-4 receptor monoclonalantibody, an anti IgE monoclonal antibody, a monoclonal antibodydirected against one or more pro-inflammatory cytokines, a TNF-αinhibitor, a fusion protein, a chemotherapeutic agent or a combinationthereof. In some embodiments, the secondary agent is ananti-inflammatory drug. In some embodiments, anti-inflammatory drugsinclude, but are not limited to, alclofenac, alclometasone dipropionate,algestone acetonide, alpha amylase, amcinafal, amcinafide, amfenacsodium, amiprilose hydrochloride, anakinra, anirolac, anitrazafen,apazone, balsalazide disodium, bendazac, benoxaprofen, benzydaminehydrochloride, bromelains, broperamole, budesonide, carprofen,cicloprofen, cintazone, cliprofen, clobetasol propionate, clobetasonebutyrate, clopirac, cloticasone propionate, cormethasone acetate,cortodoxone, curcumin, deflazacort, desonide, desoximetasone,dexamethasone dipropionate, diclofenac potassium, diclofenac sodium,diflorasone diacetate, diflumidone sodium, diflunisal, difluprednate,diftalone, dimethyl sulfoxide, drocinonide, endrysone, enlimomab,enolicam sodium, epirizole, etodolac, etofenamate, felbinac, fenamole,fenbufen, fenclofenac, fenclorac, fendosal, fenpipalone, fentiazac,flazalone, fluazacort, flufenamic acid, flumizole, flunisolide acetate,flunixin, flunixin meglumine, fluocortin butyl, fluorometholone acetate,fluquazone, flurbiprofen, fluretofen, fluticasone propionate,furaprofen, furobufen, halcinonide, halobetasol propionate, halopredoneacetate, ibufenac, ibuprofen, ibuprofen aluminum, ibuprofen piconol,ilonidap, indomethacin, indomethacin sodium, indoprofen, indoxole,intrazole, isoflupredone acetate, isoxepac, isoxicam, ketoprofen,lofemizole hydrochloride, lomoxicam, loteprednol etabonate, lysofylline,meclofenamate sodium, meclofenamic acid, meclorisone dibutyrate,mefenamic acid, mesalamine, meseclazone, methylprednisolone suleptanate,momiflumate, nabumetone, naproxen, naproxen sodium, naproxol, nimazone,olsalazine sodium, orgotein, orpanoxin, oxaprozin, oxyphenbutazone,paranyline hydrochloride, pentosan polysulfate sodium, phenbutazonesodium glycerate, pirfenidone, piroxicam, piroxicam cinnamate, piroxicamolamine, pirprofen, prednazate, prifelone, prodolic acid, proquazone,proxazole, proxazole citrate, rimexolone, romazarit, salcolex,salnacedin, salsalate, sanguinarium chloride, seclazone, sermetacin,sudoxicam, sulindac, suprofen, talmetacin, talniflumate, talosalate,tebufelone, tenidap, tenidap sodium, tenoxicam, tesicam, tesimide,tetrydamine, tiopinac, tixocortol pivalate, tolmetin, tolmetin sodium,triclonide, triflumidate, zidometacin, zomepirac sodium, aspirin(acetylsalicylic acid), salicylic acid, corticosteroids,glucocorticoids, tacrolimus, pimecorlimus, mepolizumab, prodrugsthereof, and a combination thereof. In some embodiments the tyrosinekinase inhibitor is imatinib. In some embodiments the anti IL-5monoclonal antibody is mepolizumab or reslizumab. In some embodiments,the IL-5 receptor monoclonal antibody is benralizumab. In someembodiments, the anti IL-13 monoclonal antibody is lebrikizumab ordulipumab. In some embodiments the anti IL-4 monoclonal antibody isdulipumab. In some embodiments, the anti IgE monoclonal antibody isomalizumab. In some embodiments, the TNF-α inhibitor is infliximab,adalimumab, certolizumab pegol, or golimumab. In some embodiments, thefusion protein is etanercept.

Various embodiments may also comprise an induction step comprisingadministration of a therapeutically effective amount of a secondaryagent that induces anti-inflammatory effects or is capable of decreasinglevels of eosinophils and/or basophils in the subject prior toadministration of a therapeutically effective amount of dexpramipexoleor a pharmaceutically acceptable salt thereof. In some embodiments,administration of the secondary agent may continue or may becomediscontinued once administration of dexpramipexole or pharmaceuticallyacceptable salt thereof starts.

In some embodiments, the induction step comprises administering atherapeutically effective amount of the secondary agent for a period ofabout 1 day to about 6 months. In some embodiments, the secondary agentis administered for a period of about 1 day, about 2 days, about 3 days,about 4 days, about 5 days, about 6 days, about 1 week, about 2 weeks,about 3 weeks, about 1 month, about 2 months, about 3 months, about 4months, about 5 months, or about 6 months. In some embodiments, theinduction step comprises administering a therapeutically effectiveamount of the secondary agent for a period of less than 1 week, about 1to 2 weeks, about 2 to 3 weeks, about 3 to 4 weeks, about 1 to 2 months,about 2 to 3 months, or about 3 to 4 months. In yet other embodiments,the induction step comprises administering a therapeutically effectiveamount of the secondary agent until a pre-determined level ofeosinophils and/or basophils is reached, after which the induction stepis discontinued, titrated out, or a combination thereof. In someembodiments, the induction step may use any of the methods describedherein. In some embodiments, the induction step is followed by theadministration of the dosage regimens for dexpramipexole describedherein as well as any of the compositions described herein.

In any of the embodiments described, a therapeutically effective amountof dexpramipexole or a pharmaceutically acceptable salt thereof and atherapeutically effective amount of one or more of the secondary agentsdescribed above may be provided adjunctively in separate pharmaceuticalcompositions or in a single dose pharmaceutical composition in which thedexpramipexole or a pharmaceutically acceptable salt thereof and one ormore secondary agent are combined. In some embodiments, the one or moresecondary agent is a therapeutic agent capable of decreasing levels ofeosinophils and/or basophils in the subject.

Specific modes of administration of dexpramipexole or salt thereof willdepend on the indication. The selection of the specific route ofadministration and the dose regimen may be adjusted or titrated by theclinician according to methods known to the clinician in order to obtainthe optimal clinical response. The amount of compound to be administeredmay be that amount which is therapeutically effective. The dosage to beadministered may depend on the characteristics of the subject beingtreated, e.g., the particular animal or human subject treated, age,weight, body mass index, body surface area, health, types of concurrenttreatment, if any, and frequency of treatments, and can be easilydetermined by one of skill in the art (e.g., by the clinician).

In the embodiments described herein, the therapeutically effectiveamount of dexpramipexole or pharmaceutically acceptable salt thereof maybe administered in a pharmaceutical composition. Each of thepharmaceutical compositions described herein may be used in any of themethods or dosage regimens described herein.

In some embodiments, administering a therapeutically effective amount ofdexpramipexole or a pharmaceutically acceptable salt thereof may includeadministering dexpramipexole or a pharmaceutically acceptable saltthereof in a controlled release form.

Pharmaceutical compositions containing dexpramipexole or apharmaceutically acceptable salt thereof in a solid dosage may include,but are not limited to, softgels, tablets, capsules, cachets, pellets,pills, powders and granules; topical dosage forms which include, but arenot limited to, solutions, powders, fluid emulsions, fluid suspensions,semi-solids, ointments, pastes, creams, gels and jellies, and foams; andparenteral dosage forms which include, but are not limited to,solutions, suspensions, emulsions, and dry powder; comprising aneffective amount of a polymer or copolymer of the present invention.

It is also known in the art that the active ingredients may be containedin such compositions with pharmaceutically acceptable diluents, fillers,disintegrants, binders, lubricants, surfactants, hydrophobic vehicles,water-soluble vehicles, emulsifiers, buffers, humectants, moisturizers,solubilizers, preservatives and the like. The means and methods foradministration are known in the art and an artisan can refer to variouspharmacologic references for guidance. For example, ModernPharmaceutics, Banker & Rhodes, Marcel Dekker, Inc. (1979); and Goodman& Gilman's The Pharmaceutical Basis of Therapeutics, 6th Edition,MacMillan Publishing Co., New York (1980) can be consulted.

In some embodiments, pharmaceutical compositions may be suitable fororal administration such as, for example, a solid oral dosage form or acapsule, and in certain embodiments, the composition may be a tablet.Such tablets may include any number of additional agents such as, forexample, one or more binder, one or more lubricant, one or more diluent,one or more surface active agent, one or more dispersing agent, one ormore colorant, and the like. Such tablets may be prepared by any methodknown in the art, for example, by compression or molding. Compressedtablets may be prepared by compressing in a suitable machine theingredients of the composition in a free-flowing form such as a powderor granules, and molded tablets may be made by molding in a suitablemachine a mixture of the powdered compound moistened with an inertliquid diluent. The tablets, of some embodiments, may be uncoated and,in other embodiments, they may be coated by known techniques.

In other embodiments, the pharmaceutical compositions may be provided ina dragee core with suitable coatings. In such embodiments, dragee coresmay be prepared using concentrated sugar solutions, which may optionallycontain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel,polyethylene glycol, and/or titanium dioxide, lacquer solutions, andsuitable organic solvents or solvent mixtures. In some embodiments,dyestuffs or pigments may be added to the tablets or dragee coatings foridentification or to characterize different combinations of activecompound doses. In yet other embodiments, pharmaceutical compositionsincluding a therapeutically effective amount of dexpramipexole preparedfor oral administration may include, but are not limited to, push-fitcapsules made of gelatin, as well as soft, sealed capsules made ofgelatin and a plasticizer, such as glycerol or sorbitol. The push-fitcapsules may contain the active ingredients in admixture with fillersuch as, e.g., lactose, binders such as, e.g., starches, and/orlubricants such as, e.g., talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added. Allcompositions for oral administration should be in dosages suitable forsuch administration.

In embodiments in which the tablets and dragee cores are coated, thecoatings may delay disintegration and absorption in the gastrointestinaltract and thereby providing a sustained action over a longer period.Additionally, such coatings may be adapted for release of dexpramipexoleor a pharmaceutically acceptable salt thereof in a predetermined pattern(e.g., in order to achieve a controlled release composition) or it maybe adapted not to release the active compound until after passage of thestomach (enteric coating). Suitable coatings encompassed by suchembodiments may include, but are not limited to, sugar coating, filmcoating (e.g., hydroxypropyl methylcellulose, methylcellulose, methylhydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethylcellulose,acrylate copolymers, polyethylene glycols and/or polyvinylpyrrolidone),or an enteric coating (e.g., methacrylic acid copolymer, celluloseacetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinyl acetate phthalate, shellac,and/or ethyl cellulose). Furthermore, a time delay material such as, forexample, glyceryl monostearate or glyceryl distearate may beincorporated into the coatings of some embodiments. In still otherembodiments, solid tablet compositions may include a coating adapted toprotect the composition from unwanted chemical changes, for example, toreduce chemical degradation prior to the release of the active drugsubstance.

In some embodiments, the pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beprepared as suspensions, solutions or emulsions in oily or aqueousvehicles suitable for injection. In such embodiments, such liquidcompositions may further include formulatory agents such as suspending,stabilizing and or dispersing agents formulated for parenteraladministration. Such injectable compositions may be administered by anyroute, for example, subcutaneous, intravenous, intramuscular,intra-arterial or bolus injection or continuous infusion, and inembodiments in which injectable compositions are administered bycontinuous infusion, such infusion may be carried out for a period ofabout 15 minutes to about hours. In certain embodiments, compositionsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative.

In other embodiments, dexpramipexole may be formulated as a depotpreparation, and such long acting compositions may be administered byimplantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Depot injections may be administered at about 1to about 6 months or longer intervals. In some embodiments, thefrequency of doses of the dexpramipexole described herein administeredby depot injection may be once a month, every three months, or once ayear. The compounds may be formulated with suitable polymeric orhydrophobic materials (for example, as an emulsion in an acceptable oil)or ion exchange resins, or as sparingly soluble derivatives, forexample, as a sparingly soluble salt.

In still other embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beformulated for buccal or sublingual administration. In such embodiments,the pharmaceutical compositions may be prepared as chewable tablets,flash melts or lozenges formulated in any conventional manner.

In yet other embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beformulated for administration by inhalation. In such embodiments,pharmaceutical compositions may be delivered in the form of an aerosolspray presentation from pressurized packs or a nebulizer, with the useof a suitable propellant, e.g., dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Capsules and cartridges of, e.g., gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the compoundand a suitable powder base such as lactose or starch.

In further embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beadministered intranasally or by inhalation including, but not limitedto, an intranasal spray or by pulmonary inhalation with an appropriatecarrier. One suitable route of administration is a depot form formulatedfrom a biodegradable suitable polymer, e.g.,poly-D,L-lactide-coglycolide as microcapsules, microgranules orcylindrical implants containing dispersed dexpramipexole.

In further embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beformulated in rectal compositions such as suppositories or retentionenemas, e.g., containing conventional suppository bases such as cocoabutter or other glycerides.

In some embodiments, pharmaceutical compositions includingdexpramipexole or a pharmaceutically acceptable salt thereof may beformulated for transdermal administration. For example, suchpharmaceutical compositions may be prepared to be applied to a plasteror applied by transdermal, therapeutic systems supplied to the subject.In other embodiments, pharmaceutical and therapeutic compositionsincluding dexpramipexole or a pharmaceutically acceptable salt thereoffor transdermal administration may include a suitable solid or gel phasecarriers or excipients such as, but are not limited to, calciumcarbonate, calcium phosphate, various sugars, starches, cellulosederivatives, gelatin, and polymers such as, e.g., polyethyleneglycols.In some embodiments, pharmaceutical compositions includingdexpramipexole may be administered alone as a single therapeutic agent.In other embodiments, the pharmaceutical compositions includingdexpramipexole may be administered in combination with one or more otheractive ingredients, such as, for example, adjuvants, proteaseinhibitors, or other compatible drugs or compounds where such acombination is seen to be desirable or advantageous in achieving thedesired effects of the methods described herein.

The pharmaceutical compositions described herein may be prepared,packaged, or sold in bulk as a single unit dose or as multiple unitdoses and may be administered in the conventional manner by any routewhere they are active. For example, the compositions may be administeredorally, ophthalmically, intravenously, intramuscularly,intra-arterially, intramedullary, intrathecally, intraventricularly,transdermally, subcutaneously, intraperitoneally, intravesicularly,intranasally, enterally, topically, sublingually, rectally, byinhalation, by depot injections, or by implants or by use of vaginalcreams, suppositories, pessaries, vaginal rings, rectal suppositories,intrauterine devices, and transdermal forms such as patches and creams.Specific modes of administration will depend on the indication. Theselection of the specific route of administration and the dose regimenmay be adjusted or titrated by the clinician according to known methodsin order to obtain the optimal clinical response. All of the methodsdescribed herein may be carried out by administering dexpramipexole byany such route for administration described herein. Additionally,dexpramipexole may be delivered by using any such route ofadministration for all of the dosage regimens described herein. Thecompositions and amounts of non-active ingredients in such a compositionmay depend on the amount of the active ingredient, and on the size andshape of the tablet or capsule. Such parameters may be readilyappreciated and understood by one of skill in the art.

In some embodiments, the pharmaceutical compounds may be formulatedreadily by combining these compounds with pharmaceutically acceptablecarriers well known in the art. Such carriers enable the compounds to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions and the like, for oral ingestion by a subject tobe treated. Pharmaceutical preparations for oral use may be obtained byadding a solid excipient, optionally grinding the resulting mixture, andprocessing the mixture of granules, after adding suitable auxiliaries,if desired, to obtain tablets or dragee cores. Suitable excipientsinclude, but are not limited to, fillers such as sugars, including, butnot limited to, lactose, sucrose, mannitol, and sorbitol; cellulosepreparations such as, but not limited to, maize starch, wheat starch,rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose,hydroxypropylmethylcellulose, sodium carboxymethylcellulose, andpolyvinylpyrrolidone (PVP). In some embodiments, disintegrating agentsmay be added, such as, but not limited to, the cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof such as sodiumalginate.

In some embodiments, the pharmaceutical composition may include adiluent in an amount from about 20% to about 50% by weight of saidcomposition; optionally, a second diluent in an amount from about 10% toabout 30% by weight of said composition; optionally, a disintegrant inan amount from about 2% to about 6% of said composition; optionally, alubricant in an amount from about 0.01% to about 2% of said composition;and dexpramipexole. In further embodiments, the pharmaceuticalcomposition may include any amount or combination of microcrystallinecellulose, mannitol, croscarmellose sodium, crospovidone, croscarmellosemagnesium stearate, or combination thereof. In some embodiments, thepharmaceutical composition may include microcrystalline cellulose,mannitol, croscarmellose sodium, magnesium stearate, or a combinationthereof. In other embodiments, the pharmaceutical composition mayinclude microcrystalline cellulose in an amount from about 20% to about50% by weight of said composition; mannitol in an amount from about 10%to about 30% by weight of said composition; crospovidone in an amountfrom about 2% to about 6% of said composition; magnesium stearate in anamount from about 0.01% to about 2% of said composition; anddexpramipexole.

The pharmaceutical composition may have a chiral purity fordexpramipexole of at least 99.5%, preferably at least 99.6%, preferablyat least 99.7%, preferably at least 99.8%, preferably at least 99.9%,preferably at least 99.95%, or more preferably at least 99.99%. In someembodiments, the chiral purity for dexpramipexole is 100%. In someembodiments, the composition has a chiral purity for dexpramipexole of99.9% or greater. In some embodiments, the composition has a chiralpurity for dexpramipexole of 99.95% or greater. In some embodiments, thecomposition has a chiral purity for dexpramipexole of 99.99% or greater.The high chiral purity of the pramipexole used herein, dexpramipexole,allows for therapeutic compositions that may have a wide individual anddaily dose range.

The embodiments for amounts of dexpramipexole or a pharmaceuticallyacceptable salt thereof in the pharmaceutical composition, chiralpurity, and dosage form, which are described herein separately for thesake of brevity, may be joined in any suitable combination.

In a further embodiment, a pharmaceutical composition may comprise atherapeutically effective amount of dexpramipexole or a pharmaceuticallyacceptable salt thereof and a NOAEL dose amount of (S)-pramipexole. Thepharmaceutical composition may further comprise a pharmaceuticallyacceptable carrier and/or excipient. Such embodiments may furtherinclude one or more diluent, one or more disintegrant, one or morelubricant, one or more pigment or colorant, one or more gelatin, one ormore plasticizer and the like.

In some embodiments, the NOAEL dose amount of (S)-pramipexole is lessthan about 1.50 mg. In other embodiments, the NOAEL dose amount of(S)-pramipexole is an amount that does not exceed about 1.0 mg. Incertain embodiments, the NOAEL dose amount of (S)-pramipexole is anamount that does not exceed about 0.75 mg, about 0.5 mg, about 0.25 mg,about 0.125 mg or about 0.05 mg. In some embodiments, the NOAEL doseamount of (S)-pramipexole is less than about 0.5 mg, less than about0.125 mg, or less than about 0.05 mg. In some embodiments, thetherapeutically effective amount of dexpramipexole and a NOAEL amount of(S)-pramipexole are administered in a single unit dose form.

Embodiments of the invention are not limited to any particular agentencompassed by the classes of agents described above, and any agent thatfalls within any of these categories may be utilized in embodiments ofthe invention. Non-limiting examples of such agents are provided forclarity. Any of the secondary agents described above may be useful inembodiments of the invention.

The embodiments for disease states, subject type, daily dose amounts,therapeutically effective amounts, no observable adverse effect leveldose amounts, non-effective dose amounts, pharmaceutical compositions,and chiral purities for the methods of the invention, which aredescribed herein separately for the sake of brevity, can be joined inany suitable combination.

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Specific embodiments disclosed herein may be further limited in theclaims using “consisting of” or “consisting essentially of” language,rather than “comprising”. When used in the claims, whether as filed oradded per amendment, the transition term “consisting of” excludes anyelement, step, or ingredient not specified in the claims. The transitionterm “consisting essentially of” limits the scope of a claim to thespecified materials or steps and those that do not materially affect thebasic and novel characteristic(s). Embodiments of the invention soclaimed are inherently or expressly described and enabled herein.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

EXAMPLE 1

Effects of dexpramipexole on minipig eosinophils

In a 39-week repeat-dose toxicology study, minipigs were dosed at 0,7.5, 25, and 75 mg/kg dexpramipexole by daily oral gavage through StudyDay 45 and at 0, 7.5, 25, and 50 mg/kg dexpramipexole from Study Day 46to study completion. As shown in FIG. 1, dexpramipexole produced both adose- and time-dependent reduction in eosinophils. The effects ofdexpramipexole treatment on minipig eosinophils was statisticallysignificant at 39 weeks in the 25 mg/kg group and at all time points inthe 50/75 mg/kg group. These differences were not considered adversefrom a safety perspective.

EXAMPLE 2

Eosinophil and basophil reductions in a Phase 2 trial in ALS subjects

In a Phase 2 trial in ALS, a dose- and time-dependent decrease ineosinophil counts was seen among subjects receiving dexpramipexoletreatment. The Phase 2 trial was a two-part, double-blind study thatevaluated the safety, tolerability, and clinical effects ofdexpramipexole in ALS patients.

In Part 1, subjects were randomized to placebo (n=27), 50 mg/day (n=23),150 mg/day (n=26), or 300 mg/day dexpramipexole (n=26) for 12 weeks.From baseline to week 12, mean serum eosinophils increased by 29.2% inthe placebo group and declined by 18.2% (p=0.0370), 69.9%, (p<0.0001),and 42.9% (p=0.0008) in the 50 mg, 150 mg, and 300 mg groups,respectively (FIG. 2A).

During a one-month washout following week 12, mean eosinophils at week16 recovered to 47% and 73% of baseline levels in the 150 and 300 mg/daygroups, respectively.

Following drug washout, subjects in part 2 re-randomized to 150 mg twicedaily had a greater decline in eosinophils from week 16 to week 40 thansubjects re-randomized to 25 mg twice daily (78.9% vs 17.6%, p=0.011).

EXAMPLE 3

Eosinophil-lowering and basophil-lowering effects of dexpramipexole in aPhase 3 trial

The phase 3 clinical trial was a double-blind study of dexpramipexole inALS patients randomized 1:1 to placebo or dexpramipexole 300 mg dailytreatment. Hematology parameters were collected as part of routinesafety monitoring. Eosinophil and basophil counts were retrospectivelyanalyzed by visit.

Eosinophil levels were summarized over available time points andanalyzed by ANOVA testing the effect of treatment vs. placebo on meanchanges in serum eosinophil counts from baseline. Subjects with baselineeosinophils from 0 to 0.02×10⁹/L (constituting less than 2% of allsubjects analyzed) were censored from the primary analysis because ofthe inherent limitation to observe a decline from baseline.

The eosinophil-lowering effect developed slowly, reached plateau atabout month 4, and persisted through month 12 (FIG. 2B). A profounddecrease in peripheral blood eosinophil count was observed after 8-12weeks of treatment with dexpramipexole that persisted for the durationof the trial. Statistical analysis of the change from baseline wasperformed at month 6 to remove the effect of study dropouts in latermonths. At this time point, mean eosinophil counts were 68.4% reducedfrom baseline (p<0.0001).

The effect of dexpramipexole in reducing eosinophil counts was observedin most patients, with 77.5% of dexpramipexole-treated subjectsexperiencing a 50% or greater decline in eosinophil count after 6 monthsof treatment.

ALS is not typically associated with a systemic inflammatory responseand accordingly baseline eosinophil counts in the dexpramipexole-treatedand placebo groups of 0.129 and 0.127×10⁹/L, respectively, were withinthe reference range. However, the eosinophil-lowering effect ofdexpramipexole was not diminished in subjects (n=42) with highereosinophil counts (i.e. >0.25×10⁹/L), among whom a 75% decrease wasobserved after 6 months of treatment (data not shown).

Changes in basophil counts were also analyzed in the Phase 3 trial. Asshown in FIG. 3A, basophil counts, like eosinophil counts, declinedslowly, reached plateau at about month 4, and remained reduced for theduration of treatment through month 12. At the six month analysis, meanbasophil counts were 45.5% reduced from baseline (p<0.0001).

EXAMPLE 4

Effects of dexpramipexole on ALS clinical trial subjects with baselinehypereosinophilia

Baseline parameters were reviewed in Phase 2 and Phase 3 studies ofdexpramipexole in ALS to identify subjects with significantly elevatedeosinophil counts prior to the initiation of dexpramipexole treatment.As shown in FIG. 4A, one Phase 2 subject with hypereosinophilia at Part2 baseline showed a decrease in eosinophil counts with dexpramipexoletreatment. The substantial reduction in eosinophils persisted for theperiod the subject remained on dexpramipexole through month 12.

As shown in FIG. 4B, a Phase 3 subject with elevated eosinophil countsat baseline also showed a decrease in eosinophil counts withdexpramipexole treatment. This subject had the highest baselineeosinophil count in the dexpramipexole treatment group in the Phase 3study and showed a decrease in eosinophil counts on treatment. Thesubstantial reduction in eosinophils persisted for the period thesubject remained on dexpramipexole through month 12.

EXAMPLE 5

Hematological effects of dexpramipexole

Hematological parameters were measured in a Phase 3 study ofdexpramipexole in ALS. Because of the high rate of mortality among ALSpatients, including subjects in the Phase 3 trial, hematology parametersobtained at the month 6 visit were chosen for analysis to remove theeffect of study dropouts in later months. At month 6 in the Phase 3study, all myeloid and lymphoid cell types measured showed statisticallysignificant mean reductions from baseline, although the magnitude of theeffect was greatest for eosinophils, which declined 68.4% from baseline,and basophils, which declined 45.5% from baseline (FIG. 5). Notablyamong hematology parameters, there was no effect of dexpramipexole oneither red blood cells or platelets compared to the control group.

EXAMPLE 6

Effect of dexpramipexole in a mouse model of asthma

Allergic asthma is a condition initiated by an immune response to adiverse array of allergens and is manifested by airway obstruction,hyper-reactivity, and lung inflammation. This asthmatic response can bemimicked in experimental animals by exposing them to an array ofantigens. Like the asthmatic response in humans, the animal model ofpulmonary inflammation is characterized by an extensive inflammatoryresponse, including a localized increase in cellular infiltrate andinflammatory cytokines.

A study was conducted to assess the effects of dexpramipexole in thismodel. Female 6- to 8-week-old C57BL/6 mice were untreated (Unt),treated with ovalbumin (OVA), with OVA and 30 or 100 mg/kgdexpramipexole, or dexpramipexole alone. Whole blood was collected fromeach mouse at day zero (prior to dosing), day 28 (14 days after initialOVA sensitization), and day 42 (after final OVA challenge). Samples werequantitated on a hemoanalyzer for number of cells in each subpopulationlisted.

As shown in FIG. 6, at the end of the study (day 42), circulating levelsof eosinophils were significantly reduced (p=0.0041) in the 100 mg/kgdose group compared to vehicle-treated controls. This resultdemonstrated that the mouse is a responsive animal model species as thecirculating eosinophils were lowered by dexpramipexole treatment similarto minipig and humans.

In this model, the influx of white blood cells (WBCs) to the lungs isdominated by eosinophils, according to Nials and Uddin, Disease Models &Mechanisms 1, 213-220 (2008). Bronchoalveolar lavage fluid collected atthe end of the experiment (day 42) showed a significant increase ininfiltrating white blood cells in OVA-treated mice. Samples werequantitated on a hemoanalyzer for number of white blood cells. Treatmentwith dexpramipexole at 30 and 100 mg/kg caused a dose-dependent decreasein infiltrating white blood cells. (*** p<0.001, ** p<0.01 compared toOVA, one-way ANOVA with post-hoc Dunnett's test).

What is claimed is:
 1. A method of treating asthma comprising administering to a human in need thereof a therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof.
 2. The method of claim 1, wherein the asthma is selected from atopic asthma, allergic asthma, persistent asthma, mild asthma, moderate asthma, severe asthma and any combination thereof.
 3. The method of claim 1, wherein the pharmaceutically acceptable salt is (6R)-4, 5, 6, 7-tetrahydro-N6-propyl-2,6-benzothiazolediamine dihydrochloride monohydrate.
 4. The method of claim 1, further comprising measuring the level of eosinophils in the subject's peripheral blood, tissue, or a combination thereof.
 5. The method of claim 4, wherein the level of eosinophils is selected from the group consisting of at or above 100 cells per microliter in peripheral blood, at or above 150 cells per microliter in peripheral blood, at or above 200 cells per microliter in peripheral blood, and at or above 300 cells per microliter in peripheral blood.
 6. The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is from about 50 milligrams to about 1,500 milligrams per day.
 7. The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 milligrams per day.
 8. The method of claim 1, wherein the dexpramipexole or a pharmaceutically acceptable salt thereof is administered in a solid unit dose selected from a tablet or capsule.
 9. The method of claim 1, wherein administering comprises administering a fraction of the daily dose two or more times per day.
 10. The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is administered as an initial dosing regimen followed by administration of a therapeutically effective amount of dexpramipexole or a pharmaceutically acceptable salt thereof as a maintenance dosing regimen.
 11. The method of claim 10, wherein the initial dosing regimen is administered for about 1 week to about 12 weeks.
 12. The method of claim 10, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the initial dosing regimen is from about 50 milligrams to about 1,500 milligrams per day.
 13. The method of claim 10, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the maintenance dosing regimen is from about 150 milligrams to about 300 milligrams per day.
 14. The method of claim 1, further comprising administration of an induction step.
 15. The method of claim 14, wherein said induction step comprises administering a second therapeutic agent that is capable of decreasing eosinophil levels selected from the group consisting of corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a tyrosine kinase inhibitor, a fusion protein, a monoclonal antibody directed against one or more pro-inflammatory cytokines, a chemotherapeutic agent and a combination thereof.
 16. The method of claim 14, wherein said administration of the induction step is from about 1 week to about 6 months.
 17. The method of claim 1, wherein therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is administered via a route of administration selected from the group consisting of orally, by inhalation, intranasally, via intravenous administration, topically, and any combination thereof.
 18. The method of claim 1, further comprising administering to the subject a therapeutically effective amount of one or more secondary agents.
 19. The method of claim 18, wherein the secondary agent is selected from the group consisting of a glucocorticoid, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a phenolic antioxidant, an anti-proliferative drug, a tyrosine kinase inhibitor, an anti IL-5 monoclonal antibody, an IL5 receptor monoclonal antibody, an anti IL-13 monoclonal antibody, an anti IL-13 receptor monoclonal antibody, an IL-4 monoclonal antibody, an IL-4 receptor monoclonal antibody, an anti IgE monoclonal antibody, a monoclonal antibody directed against one or more pro-inflammatory cytokines, a TNF-α inhibitor, a fusion protein, a chemotherapeutic agent, and a combination thereof.
 20. The method of claim 1, wherein the asthma is eosinophilic asthma.
 21. The method of claim 20, wherein the pharmaceutically acceptable salt is (6R)-4, 5, 6, 7-tetrahydro-N6-propyl-2,6-benzothiazolediamine dihydrochloride monohydrate.
 22. The method of claim 20, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is from about 50 milligrams to about 1,500 milligrams per day.
 23. The method of claim 20, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 300 milligrams per day.
 24. The method of claim 22, wherein administering comprises administering a fraction of the daily dose two or more times per day.
 25. The method of claim 20, wherein the dexpramipexole or a pharmaceutically acceptable salt thereof is administered in a solid unit dose selected from a tablet or capsule.
 26. The method of claim 20, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is administered as an initial dosing regimen followed by administration of a therapeutically effective amount of dexpramipexole or a pharmaceutically acceptable salt thereof as a maintenance dosing regimen.
 27. The method of claim 26, wherein the initial dosing regimen is administered for about 1 week to about 12 weeks.
 28. The method of claim 26, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the initial dosing regimen is from about 50 milligrams to about 1,500 milligrams per day.
 29. The method of claim 26, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the maintenance dosing regimen is from about 150 milligrams to about 300 milligrams per day.
 30. The method of claim 20, further comprising administration of an induction step.
 31. The method of claim 30, wherein said induction step comprises administering a second therapeutic agent that is capable of decreasing eosinophil levels selected from the group consisting of corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a tyrosine kinase inhibitor, a fusion protein, a monoclonal antibody directed against one or more pro-inflammatory cytokines, a chemotherapeutic agent and a combination thereof.
 32. The method of claim 30, wherein said administration of an induction step is from about 1 week to about 6 months.
 33. The method of claim 20, wherein therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is administered via a route of administration selected from the group consisting of orally, by inhalation, intranasally, via intravenous administration, topically, and any combination thereof.
 34. The method of claim 20, further comprising administering to the subject a therapeutically effective amount of one or more secondary agents.
 35. The method of claim 34, wherein the secondary agent is selected from the group consisting of a glucocorticoid, a corticosteroid, a non-steroidal anti-inflammatory drug (NSAID), a phenolic antioxidant, an anti-proliferative drug, a tyrosine kinase inhibitor, an anti IL-5 monoclonal antibody, an IL5 receptor monoclonal antibody, an anti IL-13 monoclonal antibody, an anti IL-13 receptor monoclonal antibody, an IL-4 monoclonal antibody, an IL-4 receptor monoclonal antibody, an anti IgE monoclonal antibody, a monoclonal antibody directed against one or more pro-inflammatory cytokines, a TNF-α inhibitor, a fusion protein, a chemotherapeutic agent, and a combination thereof.
 36. The method of claim 10, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the initial dosing regimen is from about 300 milligrams to about 600 milligrams per day.
 37. The method of claim 10, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the maintenance dosing regimen is from about 75 milligrams to about 150 milligrams per day.
 38. The method of claim 26, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the initial dosing regimen is from about 300 milligrams to about 600 milligrams per day.
 39. The method of claim 26, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, administered during the maintenance dosing regimen is from about 75 milligrams to about 150 milligrams per day.
 40. The method of claim 18, wherein the secondary agent is a corticosteroid.
 41. The method of claim 34, wherein the secondary agent is a corticosteroid.
 42. The method of claim 18, wherein the secondary agent is a monoclonal antibody selected from a group consisting of an anti IL-5 monoclonal antibody, an IL5 receptor monoclonal antibody, an anti IL-13 monoclonal antibody, an anti IL-13 receptor monoclonal antibody, an IL-4 monoclonal antibody, an IL-4 receptor monoclonal antibody, an anti IgE monoclonal antibody, a monoclonal antibody directed against one or more pro-inflammatory cytokines, and a combination thereof.
 43. The method of claim 34, wherein the secondary agent is a monoclonal antibody selected from a group consisting of an anti IL-5 monoclonal antibody, an IL5 receptor monoclonal antibody, an anti IL-13 monoclonal antibody, an anti IL-13 receptor monoclonal antibody, an IL-4 monoclonal antibody, an IL-4 receptor monoclonal antibody, an anti IgE monoclonal antibody, a monoclonal antibody directed against one or more pro-inflammatory cytokines, and a combination thereof.
 44. The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 milligrams per day.
 45. The method of claim 20, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 milligrams per day.
 46. The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 milligrams per day.
 47. The method of claim 20, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 milligrams per day.
 48. The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 milligrams twice per day.
 49. The method of claim 20, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 150 milligrams twice per day.
 50. The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 milligrams twice per day.
 51. The method of claim 20, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 75 milligrams twice per day.
 52. The method of claim 1, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 37.5 milligrams twice per day.
 53. The method of claim 20, wherein the therapeutically effective amount of dexpramipexole, or a pharmaceutically acceptable salt thereof, is about 37.5 milligrams twice per day.
 54. The method of claim 20, further comprising measuring the level of eosinophils in the subject's peripheral blood, tissue, or a combination thereof.
 55. The method of claim 54, wherein the level of eosinophils is selected from the group consisting of at or above 100 cells per microliter in peripheral blood, at or above 150 cells per microliter in peripheral blood, at or above 200 cells per microliter in peripheral blood, and at or above 300 cells per microliter in peripheral blood. 